US2012149624A1PendingUtilityA1

Subtilase Variants

55
Assignee: DRABORG HENRIETTEPriority: Nov 6, 2002Filed: Dec 20, 2010Published: Jun 14, 2012
Est. expiryNov 6, 2022(expired)· nominal 20-yr term from priority
C11D 3/386C12N 9/54
55
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Claims

Abstract

The present invention relates to novel subtilase variants exhibiting alterations relative to the parent subtilase in one or more properties including: Wash performance, thermal stability, storage stability or catalytic activity. The variants of the invention are suitable for use in e.g. cleaning or detergent compositions, such as laundry detergent compositions and dish wash compositions, including automatic dish wash compositions.

Claims

exact text as granted — not AI-modified
1 . A protease variant comprising:
 a) an insertion, substitution or deletion of one of the amino acid residues K,H,R,E,D,Q,N,C,V,L,I,P,M,F,W,Y,G,A,S,T in one or more of the positions 62, 68, 97, 98, 99, 106, 131, 170, 245, 252,   
       in combination with at least one of the following modifications 
       *0AQSVPWG; A1T,V; Q2L; S3T,A,L; V4L,A; I8V,T; S9G,D,R,K,L,V; R10H,K; V11A; Q12D; A13V; P14S,T,D,A,M,V,K,Q,L,H,R,I; A15M,T; A16P; H17R; N18S,H; R19W,K,L,F,G,I; G20*,R,A; L21F,LP,LW,LA,LG; T22S,A,K,TV,TG,TL,TW,TV,G,L,TY; G23S; S24P; K27R, V28I; V30I; I35T,V;T38S; P40L; N43D; R45H,K; G46D; A48T; S49N; F50S; V51A,I,D; P52V,A; P55S,A; S57P; G61E,D,S,R,GP; N62D,ND,NE,DE,NG,E,S; V68A,S,L,I; T71A; I72V; L75I; N76S,D; N77S; S78T; V81A; A85T; S87C; A88V,T; E89G; K94N; V95C,T; L96LA,LG; G97E,D,W,A,GG,GA,GV,N,GS; A98S,D,E,T,AS,AD,AV,AE,AH,Q,N,M,L,G,R,V,S; S99D,L,A,AD,SD,SM,SG,DA,P,G,N,C,M,V,I; G100S,GE,C; S101SA, SK; G102D,S; S103D,E,Y,L,Q,H,T; V104T,S,R,I,N,M,L,D; S106D,E,T,M,G,A,L,F,I; I107T,V,M; A108V,T,S; L111I,V; A114V; N116S,D; G118D; M119L,I,V,A,S; H120N,D,Q,K,E,Y,S; V121A; L124C; L126I; G127E; S128N,I,G,C; P129PSN,T,E,D,S,N,A; S130P,T,C,*; P131M,F,W,L,A,H,T,*,PA,S,Q,R,E,G,D,C; S132G,T; A133ASA; T134A; Q137H,E,D; A138G,V; V139L,I; N140D, K; T143A; S144D, N,P; R145G; V150I; A151V,G; A152P; A158T,V,C,E,L,D, M; G160A,D; S163G,C,N,A; Y167K,A,I; A168G; A169G; R170C,S,H,L; Y171C; A172V; N173D; A174V; M175L,I,V,A,S,T; N183D; N184D,S; N185S,D; R186L,C,H; S188G; S190A; Y192H; G195F,E; V203S,A,L,Q,M, F,I; N204T,D,S; Q206L; Y209C,H; G211D; S212N,L; T213A; Y214C,H; A215D,T; N218D,S; M222L,I,V,A,S; A223G; T224A,S; A228T; A230V; A232S,L,T,P; V234I; Q236A,L,D,T,C,M,F,S; K237R; N238D; P239T,S; S240F; S242T; V244I, M,A; Q245R,K,E,D,T,F,N,V,W,G,I,S,C,L,A,M; N248P,D,S; K251E,R; N252G,H,D,V,M,S,T,E,Y,S,Q,K,A,L; A254S; T255A,S; S256N,R,G; L257G; G258K, S259A,N,G; T260A,R; N261D; L262S, Q,V; Y263H,F; G264E; S265G,R,N; V268L,I; N269T; N296K; E271A; T274S,L,A,R, or
 b) one of the following combination variants 
 
       A108T+L111V; L124I+S125A; P129S+S130AT; L96LA+A151G+V203A; S49N+V203L+N218D; S3T+A16P+R45C+G100S+A230V; I8V+R19K+V139I; N76D+A174AL+A194P+A230V; N185R; N62NE; H120Q+Q137E, G61GE, G61GS, G100L, A133D, V68A, N123D, L111F+Y263H, V11A+G61GE+V227A+S240F, A133E+S144K+N218D, S128A+P129S+S130SP, S9R+A15T+T22TQ+S101P, S9R+A15T+H120R+Q137D+N173S, G97E, Q245W, S9R+A15T+L96LG+Q137E+Y209H, S9R+A15T+L111V+Q137E+G211D, S9R+A15T+L111I+Q137E, S9R+A15T+L111I+H120N+Q137E, S9R+A15T+L96LG+H120Q+Q137E, S9R+A15T+T260M, S9R+A15T, Q245I, S9R+A15T+H120G+Q137E+N218D, S9R+A15T+S130P, Q245F, S9R+A15T+N218D, G63E+N76D+A194P+A230V, S9R+A15T+T224A, G100S, S9R+A15T+D60DG, A138V+V139I+A194P+N218D+A230V, A108V+A169G+R170A+Y171H, I8V+P14L+R19L+V30I+I35V+S57P+P129S+Q137D+S144D+S256N, A133D+T134S+Q137A, Q137D, A98AH, V51D, Q12E+P14L+A15T, G63E+N76D+A194P+A230V, Q12E+P14L+A15T, G97GS, V51A+S163T; V139I+A151G; S9R+A15T+L96LG+S130*; A169G+R170H or
 c) one or more modifications in position 68, wherein said modification(s) comprise(s): deletion, insertion and/or substitution of an amino acid residue selected from the group consisting of K,H,R,E,D,Q,N,C,V,L,I,P,M,F,W,Y,G,A,S and T. 
 
     
     
         2 . A protease variant of  claim 1  comprising the combination of one or more of the modifications
 X62D,E,S,XD,XE,XG,DE 
 X68A,S,L,I 
 X97E,D,W,A,N,XG,XA,XV,XS 
 X98S,D,E,T,N,M,L,G,R,V,XS,XD,XV 
 X99D,L,A,P,G,N,C,M,V,I,AD,XD,XM,XG,DA 
 X106D,E,T,M,G,A,L,F,I 
 X131M,F,W,L,A,H,T,*,S,Q,R,E,G,D,C,XA 
 X170C,S,H,L 
 X245R,K,E,D,T,F,N,V,W,G,I,S,C,L,A,M 
 X252G,H,D,V,M,S,T,E,Y,S,Q,K,A,L 
 
       with at least one of the following modifications 
       *0AQSVPWG; A1T,V; Q2L; S3T,A,L; V4L,A; I8V,T; S9G,D,R,K,L,V; R10H,K; V11A; Q12D; A13V; P14S,T,D,A,M,V,K,Q,L,H,R,I; A15M,T; A16P; H17R; N18S,H; R19W,K,L,F,G,I; G20*,R,A; L21F,LP,LW,LA,LG; T22S,A,K,TV,TG,TL,TW,TV,G,L,TY; G23S; S24P; K27R, V28I; V30I; I35T,V;T38S; P40L; N43D; R45H,K; G46D; A48T; S49N; F50S; V51A,I,D; P52V,A; P55S,A; S57P; G61E,D,S,R,GP; N62D,ND,NE,DE,NG,E,S; V68A,S,L,I; T71A; I72V; L75I; N76S,D; N77S; S78T; V81A; A85T; S87C; A88V,T; E89G; K94N; V95C,T; L96LA,LG; G97E,D,W,A,GG,GA,GV,N,GS; A98S,D,E,T,AS,AD,AV,AE,AH,Q,N,M,L,G,R,V,S; S99D,L,A,AD,SD,SM,SG,DA,P,G,N,C,M,V,I; G100S,GE,C; S101SA, SK; G102D,S; S103D,E,Y,L,Q,H,T; V104T,S,R,I,N,M,L,D; S106D,E,T,M,G,A,L,F,I; I107T,V,M; A108V,T,S; L111I,V; A114V; N116S,D; G118D; M119L,I,V,A,S; H120N,D,Q,K,E,Y,S; V121A; L124C; L126I; G127E; S128N,I,G,C; P129PSN,T,E,D,S,N,A; S130P,T,C,*; P131M,F,W,L,A,H,T,*,PA,S,Q,R,E,G,D,C; S132G,T; A133ASA; T134A; Q137H,E,D; A138G,V; V139L,I; N140D, K; T143A; S144D, N,P; R145G; V150I; A151V,G; A152P; A158T,V,C,E,L,D, M; G160A,D; S163G,C,N,A; Y167K,A,I; A168G; A169G; R170C,S,H,L; Y171C; A172V; N173D; A174V; M175L,I,V,A,S,T; N183D; N184D,S; N185S,D; R186L,C,H; S188G; S190A; Y192H; G195F,E; V203S,A,L,Q,M, F,I; N204T,D,S; Q206L; Y209C,H; G211D; S212N,L; T213A; Y214C,H; A215D,T; N218D,S; M222L,I,V,A,S; A223G; T224A,S; A228T; A230V; A232S,L,T,P; V234I; Q236A,L,D,T,C,M,F,S; K237R; N238D; P239T,S; S240F; S242T; V244I, M,A; Q245R,K,E,D,T,F,N,V,W,G,I,S,C,L,A,M; N248P,D,S; K251E,R; N252G,H,D,V,M,S,T,E,Y,S,Q,K,A,L; A254S; T255A,S; S256N,R,G; L257G; G258K, S259A,N,G; T260A,R; N261D; L262S, Q,V; Y263H,F; G264E; S265G,R,N; V268L,I; N269T; N296K; E271A; T274S,L,A,R. 
     
     
         3 . The protease variant of  claim 1 , comprising one or more of the following alterations: 
       
         
           
                 
                 
               
                     
                 
                   G97E + A98S 
                   V28I + A98AD + T224S 
                 
                   G97D + A98D 
                   S99AD + M175V + P131F 
                 
                   V95C + G97W + A98E 
                   S99AD + P131L 
                 
                   V95T + G97A + A98D 
                   S9R + S99AD + P131W 
                 
                   S103Y + V104M + S106D 
                   V68A + N116S + V139L + Q245R 
                 
                   V104T + S106D 
                   S3T + A16P + R45C + G100S + A230V 
                 
                   S3T + A16P + S99SD + S144D + A158T + 
                   I8V + S9R + A15T + R19W + V30I + G61D + 
                 
                   A230V + T260R 
                   S99SD + S256N 
                 
                   S103D + V104T + S106T 
                   V30I + S99SD + S256R 
                 
                   S103D + V104L + S106M 
                   G61S + S99SD + V244I 
                 
                   S103D + V104T + S106G 
                   V68A + V139L + S163G + N185S 
                 
                   S103D + V104S + S106A 
                   S99SD + Y263H 
                 
                   S103H + V104N + S106D 
                   V104N + S106T 
                 
                   S103E + V104I + S106T 
                   S99SG + S144D 
                 
                   S103Q + V104T + S106E 
                   V30I + S99SD 
                 
                   S103E + S106T 
                   N18H + S99SD 
                 
                   S103E + V104R + S106A 
                   S9R + T22S + S99SD + K251E 
                 
                   A108T + L111V 
                   A48T + V68A + P131M 
                 
                   L124I + S125A 
                   A15M + S99SM + V139I + V244I 
                 
                   L124C + P131* 
                   P14T + A15M + S99SD 
                 
                   P129S + S130AT 
                   I8V + S99SD + S144D + A228T 
                 
                   L96LA + A151G + V203A 
                   I8V + R19K + V139I 
                 
                   S99SD + A108V + V139L 
                   I35T + N62D 
                 
                   S99SD + S190A 
                   N62D + S265G 
                 
                   S99SD + V203A 
                   Q2L + N62D 
                 
                   S99SD + V139I 
                   N62D + N76D 
                 
                   S99SD + A108V 
                   R45H + G61E + V68A 
                 
                   S99SD + S106A + A151G 
                   N62D + V121A 
                 
                   V68A + S106A 
                   N62D + A215D 
                 
                   V68A + N185D + V203S 
                   N62D + N238D 
                 
                   V68A + V139L 
                   N62D + R145G 
                 
                   V68A + V139I 
                   V4L + N62D + E89G 
                 
                   V68A + A158V 
                   N62D + S188G + K251R 
                 
                   V68A + V203A 
                   S49N + N62D 
                 
                   V68A + V203S 
                   N62NE 
                 
                   V68A + V203L + S259A 
                   V11A + N62DE 
                 
                   V68A + S106L 
                   N62ND + N184S + S256G 
                 
                   V30I + V68A + V203S 
                   N18S + N62D + I107T + A254S 
                 
                   V51A + V68A + S106T + A168G 
                   S57P + N62ND 
                 
                   V51A + V68A + S106T + A168G 
                   N62NE + V234I 
                 
                   V68A + N76S + V203M + P239T 
                   Q137H + R170C + G195E 
                 
                   V68A + V203L 
                   S99A + S101SA 
                 
                   V68A + L75I + V203Q 
                   R10K + P14A + R19K + A98AS + S128N 
                 
                   V68A + T71A + V139L 
                   T22A + R45K + A98AS + S128N 
                 
                   Y192H + V68A 
                   A98AV + S99D + Y167K 
                 
                   V68A + S106A + A108T 
                   S9G + P14K + Y167A + R170S 
                 
                   V68A + S106T + A108T 
                   S9D + P14T + Y167A + R170S 
                 
                   V68S + A108S 
                   S9R + P14M + A98AD 
                 
                   V68A + N76S + G211D 
                   S9R + R19L + A98AD + E271A 
                 
                   V68A + S106T + A108T 
                   S9R + P14S + R19F + A98AD 
                 
                   A151V + R170C 
                   S99DA + P129PSN + P131A 
                 
                   P14D + A98AS + H120D + G195F + 
                   S99AD + V244M + Q245K + N248D + 
                 
                   S212N + M222S 
                   K251R + T255A + S256N 
                 
                   S49N + V203L + N218D 
                   S9R + P14V + R19G + A98AD 
                 
                   V68A + S106M + N184D 
                   S99AD + N248P + T255A + S256G 
                 
                   P55S + V68L + A158E + G160A 
                   *0AQSVPWG + A98AD 
                 
                   V68A + A158C 
                   T22A + S99AD 
                 
                   V68A + A158L + Y214C 
                   K94N + A98T + S99L 
                 
                   A88V + S99AD + P131F 
                   N76D + A174AL + A194P + A230V 
                 
                   P14T + A16P + I72V + S99SD + V244I + T260A 
                   P40L + N218D + A232S + Q236L + Q245E + S259N 
                 
                   S99AD + P131F 
                   A232L + Q236D + Q245E 
                 
                   R10H + N62D 
                   A232T + Q236L + Q245D 
                 
                   V28I + A98AD + T224S 
                   R170H + Q236A + Q245R 
                 
                   S9K + T22K + S99AD 
                   A232L + Q236T + Q245D 
                 
                   P14S + S99AD + P131W 
                   G97GG + P131H + Q137E + V268L 
                 
                   V68A + I72V + P131F 
                   A88V + G97GV + P131H 
                 
                   S9R + S99AD 
                   G97GA + H120Q + S130P + G264E 
                 
                   S9K + S99AD 
                   G97GG + V139L 
                 
                   V28I + A88V + G100S + P131M 
                   G97GG + Q137D 
                 
                   S103L + V104S + S106G 
                   G97GG + H120D + Q137H 
                 
                   V68A + T224A 
                   N185R 
                 
                   V68A + P131F 
                   P131H + Q137E 
                 
                   A48T + V68A + P131M 
                   V104I + H120N + P131H + Q137E 
                 
                   V68A + I72V + P131F 
                   H120Q + Q137E 
                 
                   G100GE + P131F 
                   S9R + A15T + G97GV + H120D 
                 
                   S99AD + P131F + T260A 
                   G100S + H120Q + Q137H 
                 
                   R19G + A98AS 
                   V68A + H120K + Q137E 
                 
                   G61R + N62D 
                   G97GA + H120E 
                 
                   V68A + S106M + N184D 
                   H120D + S128I + Q137D 
                 
                   P55S + V68L + A158E + G160A 
                   G97GG + P131H 
                 
                   V68A + A158C 
                   G97GG + H120N + L126I 
                 
                   R19W + G61S + S99SD + N204T + Y263H + 
                   S9R + A15T + G97GA + H120D + P131H + 
                 
                   S265R 
                   Q137E 
                 
                   A232T + Q236C 
                   S9R + A15T + G97GV + P131T + Q137H 
                 
                   N62D + A232T + Q236C 
                   S9R + A15T + G20* + L21F + N62D + Q245N 
                 
                   A232P + Q236L + Q245E 
                   S9L + A15T + T22TV + V139L + Q245F 
                 
                   A232S + Q236L + Q245T + K251E 
                   S132G + Q245F 
                 
                   S163C + Q236M + Q245T + S256G 
                   S9R + A15T + T22TG + N62D + V139L + Q245V 
                 
                   N218D + A232L + Q236F + Q245F 
                   S9L + A15T + T22TV + V139L + Q245F + L262S 
                 
                   S163N + A232L + Q236S + Q245E 
                   S9R + A15T + T22TL + N62D + Q245W 
                 
                   A232S + Q236S + Q245E 
                   V68A + A158L + Y214C 
                 
                   V68A + V203L 
                   N62D + V150I 
                 
                   V68S + A158D 
                   S3T + P14Q + A15M + R19K + N62D + S144D 
                 
                   I8V + A15T + R19K + A85T + S99SD + A114V + 
                   P14Q + R19W + V51I + G61E + S99SD + 
                 
                   V244I + S256N + Y263H 
                   V139I + T260R 
                 
                   L111F + Y263H 
                   S3T + P14L + H17R + S99SD + V139I + S144D 
                 
                   P52V + S78T + S99SD 
                   S3A + V30I + S99SD + S106G + N248S 
                 
                   A15M + S99SD + V268I 
                   I8V + A15T + S99SD 
                 
                   S99G + S128N + N183D + A232L + Q236T + 
                   S3T + S9R + P14H + A15M + R19L + S99SD + 
                 
                   Q245R 
                   V139I 
                 
                   S99R + S101SA 
                   S9R + A15T + G97GG + H120D + Q137E 
                 
                   L96LA + A98T + P131AA 
                   S9R + A15T + G20A + G97GV + H120D + P131H 
                 
                   A98E + S99P 
                   S163N + A232L + Q236A + Q245G 
                 
                   V28I + S99AD + P131F 
                   N173D + A232L + Q236A + Q245N 
                 
                   S9R + A15T + G97GV + Q137H 
                   P55S + V68A + S106M + A108T + P129T 
                 
                   V81A + P131T + A133S + Q137E 
                   K27R + V68L + G118D + A158E 
                 
                   N43D + V68A + S106F + N238D 
                   A98E + S99A + S101SK 
                 
                   V68A + V203F 
                   V68A + N140D + T143A + S144N 
                 
                   V68A + S106E 
                   N62D + N140K + T143A + S144D 
                 
                   V68A + S106I 
                   S9F + P14T + R19L + A98AD 
                 
                   V68A + A158M + R170C 
                   S9V + P14R + R19F + A98AD 
                 
                   V68A + P129T + N218D 
                   S99A + S99SD + G258K + L262Q 
                 
                   V68S + P129E 
                   S87C + S99SA + S99D + P131A 
                 
                   V68S + P129D 
                   S99A + S99SD + G258K + L262Q 
                 
                   V68L + P129E + N261D 
                   V28I + S99A + *99aD + P131F 
                 
                   G97GV + H120D 
                   A85T + G102D + S106T + K237R 
                 
                   P131A + A133ASA 
                   V68A + T71A 
                 
                   L111F + Y263H 
                   G61GS 
                 
                   V11A + G61GE + V227A + S240F 
                   G100L 
                 
                   A133E + S144K + N218D 
                   A133D 
                 
                   S128A + P129S + S130SP 
                   V68A 
                 
                   G61GE 
                   N123D 
                 
                   S9R + A15T + T22TW + N204D + Q245I 
                   Q245W + N252V 
                 
                   S9R + A15T + G97GG + P131S + Q137H 
                   R45H + Y171C + Q245W + N252S 
                 
                   S9R + A15T + T22TG + N62D + V139L + Q245G 
                   G20R + A48T + R170C + Q245W + N252Q 
                 
                   S9R + A15T + T22TL + N62D + I107V + V139L + 
                   S9R + A15T + A16P + G97GA + P131S + Q137D + 
                 
                   Q245W 
                   N204S 
                 
                   S9G + A15T + G97GA + Q137H 
                   N218D + Q245W + N252E 
                 
                   S9R + A15T + V68A + Q245R 
                   G20R + R170C + Q245R + N252V 
                 
                   S9R + A15T + G97GA + H120N + S212L 
                   S9R + P14I + R19K + A98AD + T274S 
                 
                   S9R + A15T + L96LG + H120D + P131H + R186L 
                   A98AE + V203I 
                 
                   S9R + A15T + G97GA + H120D + Q137D 
                   V51A + V68A + S163G + V203A 
                 
                   N62D + N252T 
                   N62D + Q245W + N252H 
                 
                   V4A + S9R + A15T + G97GV + H120D 
                   N62D + Q245W + N252A 
                 
                   S9R + A15T + G97GV + H120D + Q137H 
                   G20R + N62D + V244I + Q245W + N252E 
                 
                   S9R + A15T + L96LG + H120N + P131H + Q137E 
                   N204D + Q245S 
                 
                   S9R + A15T + L96LG + H120D + P131S + Q137E 
                   N62D + Q245W + N252E 
                 
                   S9R + A15T + H120N + P131T + N218D 
                   N62D + Q245R + N252V 
                 
                   S9R + A15T + L21LP + T22TV + M119I + N218D + 
                   S9R + A15T + S24P + G61E + A85T + P239S + 
                 
                   Q245I 
                   Q245A 
                 
                   S9R + A15T + L96LG + H120D + G160D 
                   G102S + M222S + Q245L + N252D 
                 
                   V68A + S106A + G118D + Q245R + T255S + 
                   A15M + V30I + N62D + S99N + L111I + V244A + 
                 
                   L257G + T274L 
                   S265N 
                 
                   S9R + A15T + G61E + A85T + P239L + Q245C 
                   S9R + A15T + T22TG + N62D + V139L + Q245S 
                 
                   S9R + A15T + P131H + S144P 
                   S3T + Q12D + R19W + V30I + S106G + I107M 
                 
                   S9R + A15T + G97GA + Q137E 
                   V68A + A88T + V139L 
                 
                   S9R + A15T + G97GA + H120Q + P131H + Q137E 
                   V51I + L111I + G118D + Q245R 
                 
                   S9R + A15T + L21LW + G100S + V139L + Q245V 
                   V68A + V203L 
                 
                   S9R + A15T + G97GA + Q137H + N218S 
                   A1T + V68A + N116D + G118D 
                 
                   S9R + A15T + L96LG + H120N + P131S + Q137H 
                   V68A + G118D + Q245R 
                 
                   S9R + A15T + G97GA + H120N + Q137E 
                   N62D + V139I + N183D + N185S + V203I + 
                 
                     
                   Q245R + L262S 
                 
                   S9R + A15T + L96LG + P131T + Q137H 
                   N62D + I72V 
                 
                   S9R + A15T + L96LG + H120N + P131S 
                   N62D + V81A + Q245R 
                 
                   S9R + A15T + V68A + Q137D 
                   T22A + V68A + S106T + G118D 
                 
                   S9R + A15T + G97GA + H120Y + Q137H 
                   V68A + L111I + V203I 
                 
                   S9R + A15T + G97GA + Q137D 
                   G61E + V68A + A169G 
                 
                   S9R + A15T + K94N + H120N + P131H 
                   V68A + L111V 
                 
                   S9R + A15T + L96LG + P131H + Q137D 
                   V68A + G118D + V203A + K251R 
                 
                   S9R + A15T + F50S + H120D + P131H 
                   V68A + G118D 
                 
                   S9R + A15T + G97GA + H120N + Q137D + N248D 
                   A1V + V51A + V68A + V203I 
                 
                   S9R + A15T + L96LG + P131Q + Q137D 
                   V68A + V139L + A223G 
                 
                   S9R + A15T + T22G + V139L + Q245L 
                   N62D + Y214H + K237R 
                 
                   V139L + Q245R 
                   V68A + S106A + G118D + Q245R 
                 
                   S9R + A15T + Q245F 
                   S9R + A15T + T22A + N62D 
                 
                   S9R + A15T + Q245S 
                   A98Q + S99D 
                 
                   S9R + A15T + G97GV + H120Q 
                   S9R + P14I + R19K + A98AD 
                 
                   S9R + A15T + G97GA + Q137E + L262V 
                   S9R + A15M + A16P + T22S + S99AD 
                 
                   S9R + A15T + G127E + P131R + Q137H 
                   S99AD + T255R + S256N 
                 
                   S9R + A13V + A15T + I35V + N62D + Q245F 
                   S9R + A15T + T22TQ + S101P 
                 
                   S9R + A15T + Q245V 
                   S9R + A15T + H120R + Q137D + N173S 
                 
                   V139L + Q245F 
                   G97E 
                 
                   S9R + A15T + T22A + V139L + Q245E 
                   Q245W 
                 
                   S9R + A15T + T22L + V139L + Q245V + A254S 
                   S9R + A15T + L96LG + Q137E + Y209H 
                 
                   S9R + R19L + A98AD 
                   S9R + A15T + L111V + Q137E + G211D 
                 
                   P14R + A98AD 
                   S9R + A15T + L111I + Q137E 
                 
                   S9R + A15T + Q245L 
                   S9R + A15T + L111I + H120N + Q137E 
                 
                   S9R + A15T + G61E + A85T + P239S + Q245V 
                   S9R + A15T + L96LG + H120Q + Q137E 
                 
                   S9R + A15T + G61E + A85T + Q206L + Q245R 
                   S9R + A15T + T260M 
                 
                   P239T + Q245R 
                   S9R + A15T 
                 
                   S9R + A15T + N62NG + Q245T 
                   Q245I 
                 
                   S9R + A15T + G61GP + Q245L 
                   S9R + A15T + H120G + Q137E + N218D 
                 
                   S9R + A15T + G61E + A85T + Q137H + Y209C + 
                   I8V + P14L + R19L + V30I + I35V + S57P + 
                 
                   Q245G 
                   P129S + Q137D + S144D + S256N 
                 
                   S9R + A15T + G61E + A85T + P239S + Q245C 
                   Q245F 
                 
                   V68I + A98AD 
                   S9R + A15T + N218D 
                 
                   V68A + N269K 
                   G63E + N76D + A194P + A230V 
                 
                   N62D + Q245A + N252G + S265G 
                   S9R + A15T + T224A 
                 
                   N218D + Q245G + N252H 
                   G100S 
                 
                   S9R + A15T + G102S + M175T + Q245R + N252D 
                   S9R + A15T + D60DG 
                 
                   S9R + A15T + N62D + Q245W + N252V 
                   A138V + V139I + A194P + N218D + A230V 
                 
                   S9R + A15T + N62D + Q245R + N252M 
                   A108V + A169G + R170A + Y171H 
                 
                   S9R + A15T + N62D + Q245W + N252S 
                   S9R + A15T + S130P 
                 
                   S99SD + N204S + Q245R 
                   A133D + T134S + Q137A 
                 
                   N62D + Q245R 
                   Q137D 
                 
                   N62D + A151G 
                   A98AH 
                 
                   V68A + S106T 
                   V51D 
                 
                   S99A + S99SD + V203L 
                   Q12E + P14L + A15T 
                 
                   A98AD + A215T 
                   G63E + N76D + A194P + A230V 
                 
                   N62D + Q245G + N252T 
                   Q12E + P14L + A15T 
                 
                   A152P + Q245R + N252T 
                   G97GS 
                 
                   S163N + T213A + Q245R 
                   Q245W + N252Y 
                 
                   S106L + Q245R + N252E 
                   A169G + R170H 
                 
                   S9V + P14R + R19F + A98AD 
                   Q12E + P14L + A15T 
                 
                   S9R + A15T + L111I + Q137E 
                   P14R + A98AD 
                 
                   S9R + A15T + G97GA + Q137E 
                   G100S 
                 
                   S9R + A15T + L96LG + Q137E + Y209H 
                   A169G + R170H 
                 
                   S9R + A15T + L96LG + H120N + P131S 
                   A98AD + A169G 
                 
                   S9R + A15T + G97GV + H120Q 
                   A138V + V139I + A194P + N218D + A230V 
                 
                   S9R + A15T + L96LG + H120Q + Q137E 
                   S99A + S99SD + V203L 
                 
                   S9R + A15T + G97GV + P131S 
                   V68A + S106T 
                 
                   S9R + A15T + K94N + H120N + P131H 
                   A98AD + A215T 
                 
                   S9R + A15T + N76S + L111V + P131H + Q137D 
                   A108V + A169G + R170A + Y171H 
                 
                   S9R + A15T + F50S + H120D + P131H 
                   S3L + N62D + S163A + S190A 
                 
                   S9R + A15T + L96LG + S130* 
                   S9R + P14I + R19K + A98AD + T274S 
                 
                   S9R + A15T + T22TL + N62D + I107V + V139L + 
                   S9R + A15T + G61E + A85T + N218D + P239S + 
                 
                   Q245W 
                   Q245L 
                 
                   S9R + A15T + G97GA + H120D + Q137H + 
                   S9R + A15T + S24P + G61E + A85T + P239S + 
                 
                   M222V 
                   Q245A 
                 
                   S9R + A15T + G97GA + H120N + Q137D + N248D 
                   S99SD + P131F 
                 
                   S9R + A15T + L21LW + G100S + V139L + Q245V 
                   N62D + P131F + A172V 
                 
                   S9R + A15T + G20* + L21F + N62D + Q245N 
                   N62D + P131F 
                 
                   S9R + A15T + L21LC + V139L + R186H + Q245M 
                   V68A + A88T + V139L 
                 
                   S132G + Q245F 
                   V68A + G118D + V203A 
                 
                   S9R + A15T + T22TG + N62D + V139L + Q245G 
                   P40L + V68A + A108T + A138V + V203I 
                 
                   S9R + A15T + L96LG + P131Q + Q137D 
                   I8T + A98AD + T274R 
                 
                   S9R + A15T + T22TQ + S101P 
                   A98AE + V203I 
                 
                   S9R + A15T + T22TG + N62D + V139L + Q245V 
                   V51A + V68A + S163G + V203A 
                 
                   S9R + A15T + T22TL + N62D + Q245W 
                   A1V + V51A + V68A + V203I 
                 
                   S9R + A15T + T22TW + N204D + Q245I 
                   V68A + G100S 
                 
                   S9R + A15T + T22TG + N62D + V139L + Q245S 
                   V68A + V203L 
                 
                   S9R + A15T + S130P 
                   A1T + V68A + N116D + G118D 
                 
                   Q245W 
                   N62D + A169G + V203I + Q245R 
                 
                   S9R + A15T + L21LP + T22TY + V139L + G160D + 
                   G23S + S99SD + A194P + S242T + Q245R + 
                 
                   Q245L 
                   T274R 
                 
                   S9R + A15T + G61E + A85T + P239L + Q245C 
                   S99SD + N204S + Q245R 
                 
                   S9R + A15T + L21LP + T22TV + M119I + N218D + 
                   N62D + V139I + N183D + N185S + V203I + 
                 
                   Q245I 
                   Q245R + L262S 
                 
                   S9R + A15T + V68A + Q245R 
                   V68A + S106A + G118D + Q245R 
                 
                   S9R + A15T + T22A + V139L + Q245E 
                   V51I + L111I + G118D + Q245R 
                 
                   V139L + Q245R 
                   N62D + Q245R 
                 
                   S9R + A15T + Q245F 
                   N62D + I72V 
                 
                   S9R + A15T + Q245S 
                   S9R + R19L + A98AD 
                 
                   S9R + A15T + T260M 
                   S9G + P14R + R19I + A98AD 
                 
                   S9R + A15T 
                   S9R + A15T + T22L + V139L + Q245V + A254S 
                 
                   S9R + A15T + L21LG + T22TV + V139L + N204D + 
                   S99G + S128N + N183D + A232L + Q236T + 
                 
                   Q245N 
                   Q245R 
                 
                   V139L + Q245F 
                   S9R + A15T + Q245L 
                 
                   S9R + A15T + T22G + V139L + Q245L 
                   S9R + A15T + N62NG + Q245T 
                 
                   S9R + A15T + Q245V 
                   S9R + A15T + N62ND + V139L + Q245E 
                 
                   Q245F 
                   S9R + A15T + N62ND + V139L + N261D 
                 
                   S9R + Q245C 
                   Y167I + R170L + Q245E 
                 
                   S9R + A15T + N218D 
                   Y167I + R170L + Q245R 
                 
                   S9R + A13V + A15T + I35V + N62D + Q245F 
                   Y167I + R170L + Q245M 
                 
                   S9R + A15T + T224A 
                   Y167I + R170L 
                 
                   S163N + A232L + Q236A + Q245G 
                   S99SE + Q245R 
                 
                   S9R + A15T + A16P + G97GA + P131S + Q137D + 
                   S9R + A15T + G61E + A85T + Q137H + Y209C + 
                 
                   N204S 
                   Q245G 
                 
                   N218D + A232L + Q236F + Q245F 
                   S9R + A15T + G61E + A85T + P239S + Q245C 
                 
                   S163N + A232L + Q236S + Q245E 
                   G102S + M222S + Q245L + N252D 
                 
                   G97GA + H120E 
                   N62D + Q245A + N252G + S265G 
                 
                   G97GG + P131H 
                   N62D + Q245G + N252T 
                 
                   S9R + A15T + G97GA + H120D + P131H + Q137E 
                   S9R + A15T + N62D + Q245W + N252V 
                 
                   S9R + A15T + G97GV + Q137H 
                   S9R + A15T + N62D + Q245R + N252M 
                 
                   S9R + A15T + G97GV + H120N 
                   S9R + A15T + N62D + Q245W + N252S 
                 
                   S9R + A15T + G97GG + P131S + Q137H 
                   S163N + T213A + Q245R 
                 
                   S9R + A15T + G97GG + H120N + Q137D 
                   S106L + Q245R + N252E 
                 
                   S9R + A15T + H120Q + P131C + Q137H 
                   Q245W + N252Y 
                 
                   S9R + A15T + G97GV + H120D + Q137H 
                   Q245W + N252V 
                 
                   S163C + Q236M + Q245T + S256G 
                   G20R + A48T + R170C + Q245W + N252Q 
                 
                   S9R + A15T + G97GG + H120D + P131H + 
                   N62D + N252T 
                 
                   Q137H 
                 
                   S9R + A15T + G97GV + H120E + Q137H 
                   N218D + Q245W + N252E 
                 
                   S9R + A15T + G97GV + P131T + Q137H 
                   G20R + R170C + Q245R + N252V 
                 
                   S9R + A15T + G97GV + H120Q + Y263F 
                   N62D + Q245W + N252H 
                 
                   S9R + A15T + G97GV + S106A + P131H 
                   N62D + Q245W + N252A 
                 
                   S9R + A15T + G97GG + L111I + P131T + Q137H 
                   G20R + N62D + V244I + Q245W + N252E 
                 
                   S9R + A15T + G97GV + P131H + Q137H 
                   N204D + Q245S 
                 
                   S9R + A15T + G20A + G97GV + H120D + P131H 
                   N62D + Q245W + N252E 
                 
                   S9R + A15T + G97GA + H120D + P131S + Q137E 
                   N62D + Q245R + N252V 
                 
                   S9G + A15T + G97GA + Q137H 
                   A98L + S99C + Q245R 
                 
                   S9R + A15T + H120R + Q137D + N173S 
                   N62D + A98R + Q245R 
                 
                   S9R + A15T + L96LG + H120N + P131H + Q137E 
                   S9R + A15T + V68A + S99G + Q245R + N261D 
                 
                   S9R + A15T + L96LG + H120D + P131S + Q137E 
                   S9R + A15T + G20* + L21F + N62D + Q245R 
                 
                   S9R + A15T + H120N + P131T + N218D 
                   S9R + A15T + G20* + L21F + N62E + Q245R 
                 
                   S9R + A15T + G97GA + H120D + Q137D 
                   V68I + A98AD 
                 
                   S9R + A15T + L96LG + H120D + P131H + R186L 
                   S9R + A15T + H120D + Q137D 
                 
                   S9R + A15T + G97GA + R186C 
                   S9R + A15T + N77S + L96LG + H120D + P131Q 
                 
                   V4A + S9R + A15T + G97GV + H120D 
                   S9R + A15T + G97GA + H120N + Q137E 
                 
                   S9R + A15T + L96LG + H120D + G160D 
                   S9R + A15T + G97GA + Q137E + L262V 
                 
                   S9R + A15T + G97GA + H120N + S212L 
                   S9R + A15T + P131H + S144P 
                 
                   S9R + A15T + G97GA + Q137H + N218S 
                   S9R + A15T + G127E + P131R + Q137H 
                 
                   M222S + Q245G + N252G 
                   S9R + A15T + V68A + S99G + Q245R + N261D 
                 
                   V68I + V203L 
                   N62D + P131F + A172V 
                 
                   V51A + S163T 
                   N62D + P131F 
                 
                   S106A + A138G 
                   S99SD + Q245R 
                 
                   V139I + A151G 
                   S9R + A13T + S99A + S99SD + P131F 
                 
                   A98R + G100C + Q245R 
                   S9R + A15T + N62S + H120N + P131T + N218D 
                 
                   S9R + A15T + S99G + G100S + H120N + P131S + 
                   S9R + A15T + S99C + H120N + P131S + Q137H + 
                 
                   Q137H 
                   M222S 
                 
                   A15T + N185D + M222S + Q245R + N252V 
                   A98G + S99C + Q245R 
                 
                   S9R + A15T + T22TL + G61E + L96LG + Q137D + 
                   A98T + S99G + G100S + S240F + Q245R 
                 
                   Q245R 
                 
                   S9R + T22TL + G61E + G97GG + M119I + P131T 
                   S9R + A15T + H120N + P131T + N218D + N269T 
                 
                   Y209H + M222S + Q245G + N252L 
                   M222S + Q245M + N252E 
                 
                   S9R + A15T + G61E + H120S + Q137D + V139L + 
                   S9R + A15T + L96LG + H120N + P131S + Q137H + 
                 
                   N218D 
                   M222S 
                 
                   S9R + A15T + N62D + H120N + P131T 
                   S9R + A15T + G61E + A98S + S99M + Q245R 
                 
                   S9R + A15T + V68A + N218D + Q245R 
                   A98G + G100S + Q245R + N261D 
                 
                   S9R + A15T + V68A + H120N + N218D + Q245R 
                   S9R + A15T + V68A + A98L + Q245R 
                 
                   S9R + A15T + V68A + A174V + Q245R 
                   S9R + A15T + V68A + A98G + S99V + Q245R 
                 
                   S9R + A15T + G46D + V68A + N218D + Q245R 
                   S9R + A15T + V68A + A98M + Q245R + N248D 
                 
                   G97D + A98N + S128G + S130T + P131D + T134A 
                   S9R + A15T + G61E + V68A + A98S + S99G + 
                 
                     
                   Q245R 
                 
                   S9R + A15T + V68A + A98M + S99G + Q245R + 
                   S9R + A15T + A88V + A98R + S99G + G100C + 
                 
                   T274A 
                   H120N + P131S + Q137H 
                 
                   S9R + A15T + V68A + A98L + S99G + Q245R 
                   A98V + S99C + Q245R 
                 
                   S9R + A15T + A98G + S99C + H120N + P131S + 
                   S9R + A15T + G20* + L21F + G61E + *61aP + 
                 
                   Q137H 
                   Q245R 
                 
                   S9R + A15T + T38S + A98R + S99C + G100S + 
                   S9R + A15T + V68A + A98G + S99I + K237R + 
                 
                   H120N + P131S + Q137H 
                   Q245R 
                 
                   S9R + A15T + A98C + G100S + H120N + P131S + 
                   S9R + A15T + V68A + H120N + P131S + Q137H + 
                 
                   Q137H 
                   Q245R 
                 
                   S9R + A15T + A98S + G100S + H120N + P131S + 
                   S9R + A15T + V68A + H120D + P131S + Q137H + 
                 
                   Q137H 
                   Q245R 
                 
                   S9R + A15T + G20* + L21F + N62D + Q245R 
                   A98S + S99G + G100S + Q245R 
                 
                   S9R + A15T + G20* + L21F + N62D + Q245R + 
                   S9R + A15T + A98S + S99G + G100S + H120N + 
                 
                   S259G 
                   P131S + Q137H 
                 
                   A98S + G100S + Q245R 
                   A98T + S99G + G100S + Q245R 
                 
                   S9R + A15T + G20* + L21F + *61aA + V68A + 
                   S9R + A15T + G20* + L21F + P52T + N62D + 
                 
                   Q245R 
                   Q245R 
                 
                   S9R + A15T + G20* + L21F + N62E + Q245R 
                   A98L + S99C + Q245R 
                 
                   V68A + S105G + S106A 
                   V68A + S106A + T213A 
                 
                   S9R + A15T + Y167I + R170L 
                   S9R + A15T + V68A 
                 
                   V68A + S106A + N252M + Y263C 
                   V68A + S106A + Q245W 
                 
                   V68A + S106A + Q245R + N252D 
                   V68A + S106A + Q245W + N252K 
                 
                   V68A + S106A + A174V + Q245R + N252D 
                   S9R + A15T + V68A + Q245R + N252S 
                 
                   S9R + A15T + V28I + V68A + Q245R + N252A 
                   S9R + A15T + V68A + A194T + Q245R + N252E 
                 
                   S9R + A15T + G20* + L21F + *63aG + Q245R + 
                   S9R + A15T + G20* + L21F + *62aS + N218D + 
                 
                   N272V 
                   Q245R 
                 
                   S9R + A15T + G20* + L21F + *61aS + V68A + 
                   S9R + A15T + V68A + H120N + P131S + Q137H + 
                 
                   G160D + Q245R 
                   Q245M 
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       wherein
 (a) the variant has protease activity, and 
 (b) each position corresponds to a position of the amino acid sequence of subtilisin BPN′, shown in SEQ ID NO: 1. 
 
     
     
         4 . The protease variant of  claim 1 , wherein the parent subtilase belongs to the sub-group I-S1. 
     
     
         5 . The protease variant of  claim 1 , wherein the parent subtilase belongs to the sub-group 1-S2, and wherein the parent subtilase preferably is subtilisin 309. 
     
     
         6 . The protease variant of  claim 1 , wherein said variant further comprises one or more of the modifications K27R, *36D, S56P, N62D, V68A, N76D, S87N, G97N, S99SE, S101G, S103A, V104A, V104I, V104N, V104Y, S106A, H120D, H120N,N123S, G159D, Y167A, R170S, R170L, A194P, N204D, V205I, Q206E, L217D, N218S, N218D, M222S, M222A, T224S, A232V, K235L, Q236H, Q245R, N248D, N252K, T274A, S101G+V104N, S87N+S101G+V104N, K27R+V104Y+N123S+T274A, N76D+S103A+V104I, S99D+S101R+S103A+V104I+G160S, S3T+V4I+S99D+S101R+S103A+V104I+G160S+V199M+V205I+L217D, S3T+V4I+S99D+S101R+S103A+V104I+G160S+A194P+V199M+V205I+L217D, S3T+V4I+S99D+S101R+S103A+V104I+G160S+V205I and N76D+V104A. 
     
     
         7 . The protease variant of  claim 1 , comprising the following substitutions: S101G+S103A+V104I+G159D+A232V+Q236H+Q245R+N248D+N252K. 
     
     
         8 . A cleaning or detergent composition, preferably a laundry or dish wash composition, comprising a protease variant of  claim 1  and a surfactant. 
     
     
         9 . A composition of  claim 8 , which additionally comprises one or more of an amylase, cellulase, cutinase, esterase, beta-galactosidase, glycoamylase, hemicellulase, lactase, ligninase, lipase, polygalacturonase, and protease. 
     
     
         10 . An isolated DNA sequence encoding a protease variant of  claim 1   
     
     
         11 . An expression vector comprising the isolated DNA sequence of  claim 10 . 
     
     
         12 . A microbial host cell transformed with the expression vector of  claim 11 . 
     
     
         13 . A microbial host cell of  claim 12 , which is a bacterium, preferably a  Bacillus , especially a  B. lentus.    
     
     
         14 . A microbial host cell of  claim 12 , which is a fungus or yeast, preferably a filamentous fungus, especially an  Aspergillus.    
     
     
         15 . A method for producing a protease variant, comprising
 (a) culturing a host of  claim 12  under conditions conducive to the expression and secretion of the variant, and   (b) recovering the protease variant.

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