Innovative discovery of therapeutic, diagnostic, and antibody compositions related to protein fragments of histidyl-trna synthetases

Abstract

Provided are compositions comprising newly identified protein fragments of aminoacyl-tRNA synthetases, polynucleotides that encode them and complements thereof, related agents, and methods of use thereof in diagnostic, drug discovery, research, and therapeutic applications.

1 - 125 . (canceled) 
     
     
         126 . A therapeutic composition, comprising an isolated aminoacyl-tRNA synthetase (AARS) polypeptide of about 100 to about 750 amino acids in length and comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 98%, or 100% identical to a sequence in any of Table(s) 1-3, or Table(s) 4-6, or Table(s) 7-9, wherein the polypeptide has a solubility of at least about 5 mg/mL, and wherein the composition has a purity of at least about 95% on a protein basis and less than about 10 EU endotoxin/mg protein. 
     
     
         127 . The therapeutic composition of  claim 126 , wherein the polypeptide specifically binds to a binding partner to exert a physiological effect. 
     
     
         128 . The therapeutic composition of  claim 126 , wherein said polypeptide differs from an amino acid sequence set forth in any of Table(s) 1-3, or Table(s) 4-6, or Table(s) 7-9, by substitution, deletion, and/or addition of about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 amino acids, and wherein the altered polypeptide substantially retains a non-canonical activity of the unaltered protein. 
     
     
         129 . The therapeutic composition of  claim 126 , wherein the AARS polypeptide is fused to a heterologous polypeptide. 
     
     
         130 . The therapeutic composition of  claim 126 , wherein at least one moiety or a solid substrate is covalently or non-covalently attached to said polypeptide. 
     
     
         131 . An isolated aminoacyl-tRNA synthetase (AARS) polypeptide of about 100 to about 750 amino acids in length and comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 98%, or 100% identical to a sequence in any of Table(s) 1-3, or Table(s) 4-6, or Table(s) 7-9. 
     
     
         132 . The isolated AARS polypeptide of  claim 131 , wherein the AARS polypeptide is fused to a heterologous polypeptide. 
     
     
         133 . A system, comprising a substantially pure aminoacyl-tRNA synthetase (AARS) polypeptide of  claim 131 , and an element selected from the group consisting of
 (i) a binding partner that binds to the AARS polypeptide,   (ii) an engineered population of cells in which at least one cell comprises a polynucleotide encoding said AARS polypeptide, wherein the cells are capable of growing in a serum-free medium,   (iii) a cell that comprises a cell-surface receptor or an extracellular portion thereof that binds to the polypeptide, and a molecule of less than about 2000 daltons, or a second polypeptide, which modulates binding or interaction of the AARS polypeptide and the extracellular receptor,   (iv) a cell that comprises a cell-surface receptor or an extracellular portion thereof that specifically binds to the AARS polypeptide, wherein the cell comprises an indicator molecule that allows detection of a change in the levels or activity of the cell-surface receptor or extracellular portion thereof, and   (v) an engineered population of cells in which at least one cell comprises a polynucleotide encoding said AARS polypeptide, at least about 10 liters of a serum-free growth medium, and a sterile container.   
     
     
         134 . A method of determining presence or levels of an AARS polypeptide in a sample, comprising contacting the sample with one or more binding agents that specifically bind to an AARS polypeptide as set forth in any of Table(s) 1-3, or Table(s) 4-6, or Table(s) 7-9, detecting the presence or absence of the binding agent, and thereby determining the presence or levels of the AARS polypeptide. 
     
     
         135 . A method of modulating a cellular activity of a cell, or protein, comprising contacting the cell or protein with an AARS polypeptide  claim 131 , or a composition comprising a pharmaceutically-acceptable carrier and said AARS polypeptide. 
     
     
         136 . The method of  claim 135 , wherein the cell or protein is in a subject having a disease or disorder mediated by the dysregulation of the expression, activity or spatiotemporal location of a tRNA synthetase, comprising administering the AARS polypeptide or the pharmaceutical composition to the subject. 
     
     
         137 . The method of  claim 136 , wherein the disease is selected from cancer, neuropathy, diabetes, and inflammatory disorders. 
     
     
         138 . An engineered full length aminoacyl-tRNA synthetase (AARS) protein comprising a heterologous proteolysis site to enable the proteolytic generation of an AARS polypeptide as set forth in any of Table(s) 1-3, or Table(s) 4-6, or Table(s) 7-9. 
     
     
         139 . A composition, comprising a binding agent that specifically binds to an isolated aminoacyl-tRNA synthetase (AARS) polypeptide fragment as set forth in any of Table(s) 1-3, or Table(s) 4-6, or Table(s) 7-9, wherein the binding agent has an affinity of at least about 1 nM for the polypeptide fragment.