Transducible polypeptides for modifying metabolism

Abstract

Methods and compositions for modifying the metabolism of a subject are provided. One embodiment provides a recombinant polypeptide having a polynucleotide-binding domain, a protein transduction domain, and a targeting domain. In a preferred embodiment, the polynucleotide-binding domain includes one or more HMG box domains.

1 . A method for increasing mitochondrial biogenesis comprising:
 contacting one or more cells with an effective amount of a recombinant polypeptide comprising a polynucleotide-binding domain, a protein transduction domain, and a targeting domain to increase mitochondrial transcription.   
     
     
         2 . The method of  claim 1 , wherein the polynucleotide binding domain comprises a mitochondrial transcription factor or a fragment thereof that binds to a polynucleotide. 
     
     
         3 . The method of  claim 2 , wherein the mitochondrial transcription factor comprises a portion of TFAM effective to bind a polynucleotide. 
     
     
         4 . The method of  claim 1 , wherein the targeting domain comprises a portion of bacterial Protein A sufficient to bind an Fc portion of mammalian antibodies. 
     
     
         5 . The method of  claim 4 , wherein the portion of bacterial Protein A is operably linked to an antibody specific for a cell surface antigen. 
     
     
         6 . The method of  claim 5 , wherein the antibody provides tropism to the recombinant polypeptide for a target cell type or cell state. 
     
     
         7 . The method of  claim 1 , wherein the targeting domain comprises a polypeptide having 80-100% sequence identity to a targeting signal selected from the group consisting of Surfactant proteins A and B, Artery wall binding peptide, Asialoglycoproteins, Synthetic galactosylated ligands, Lectins, Anti-CD 3, Anti-CD 5, hyaluronic acid fragments, Steel factor, Anti CD117, EGF, EGF peptide Anti EGF-R, TGF-alpha, anti ErbB2, IgG, basic FGF, Folate, Malarial circumsporozoite protein, Anti HER2, Insulin, RGD peptide, Receptor associated protein (RAP), Synthetic ligands, mannosylated, NGF derived synthetic peptide, Antibody ChCE7, Antibody OV-TL 16 Fab′ fragment, anti-PECAM antibody, Anti-secretory component, peptide ligand, Anti-IgG, Anti-idiotype, Anti-thrombomodulin, Anti-Tn, and Transferrin. 
     
     
         8 . The method of  claim 1 , wherein the contacting occurs in vitro or in vivo. 
     
     
         9 . The method of  claim 7 , wherein the polypeptide comprises a portion of TFAM effective to bind the polynucleotide. 
     
     
         10 . A method for reducing body weight of a subject comprising:
 administering an effective amount of a fusion protein comprising a polynucleotide-binding domain, a protein transduction domain, and a targeting domain to the subject to increase mitochondrial oxidative metabolism in the subject.   
     
     
         11 . The method of  claim 10 , wherein the polynucleotide binding domain comprises a mitochondrial transcription factor or a fragment thereof that binds to a polynucleotide. 
     
     
         12 . The method of  claim 11 , wherein the mitochondrial transcription factor comprises a portion of TFAM effective to bind a polynucleotide. 
     
     
         13 . The method of  claim 10 , wherein the targeting domain comprises a portion of bacterial Protein A sufficient to bind an Fc portion of mammalian antibodies. 
     
     
         14 . The method of  claim 13 , wherein the portion of bacterial Protein A is operably linked to an antibody specific for a cell surface antigen. 
     
     
         15 . The method of  claim 14 , wherein the antibody provides tropism to the fusion polypeptide for a target cell type or cell state. 
     
     
         16 . The method of  claim 16 , wherein the polypeptide comprises a portion of TFAM effective to bind the polynucleotide. 
     
     
         17 . A fusion polypeptide comprising a protein transduction domain operably linked to an antibody binding domain, wherein the antibody binding domain is operably linked to a polynucleotide-binding domain or a fragment thereof effective to bind to a polynucleotide. 
     
     
         18 . The fusion polypeptide of  claim 17  comprising the amino acid sequence of SEQ ID NO: 17 or the amino acid of SEQ ID NO: 17 containing a conservative substitution. 
     
     
         19 . A composition comprising an antibody or antigen-binding fragment thereof bound to the fusion polypeptide of  claim 18  via an Fe region of the antibody or antigen-binding fragment thereof. 
     
     
         20 . The composition of  claim 19  wherein the fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 17 or the amino acid sequence of SEQ ID NO: 17 containing an conservative substitution.