Cryptic polypeptides and uses thereof

Abstract

The disclosure features, among other things, polypeptides comprising a Cryptic polypeptide, a functional fragment thereof, or variants of any of the foregoing. Also featured are nucleic acids encoding the polypeptides, methods for producing of the polypeptides, and a variety of diagnostic and therapeutic applications in which the polypeptides are useful. For example, the polypeptides can be used to treat a subject having a condition associated with bone loss.

What is claimed is: 
     
         1 . A method for treatment of a metabolic disorder, the method comprising: administering to a subject having a metabolic disorder a fusion polypeptide in an amount sufficient to treat the metabolic disorder, wherein the fusion polypeptide comprises:
 an amino-terminal region, wherein the amino-terminal region comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 20; and   a carboxy-terminal heterologous moiety, wherein the carboxy-terminal heterologous moiety provides for an increase in serum half-life of the fusion polypeptide compared to a peptide comprising the amino-terminal region without the carboxy-terminal heterologous moiety.   
     
     
         2 . The method of  claim 1 , wherein the metabolic disorder is type 2 diabetes, noninsulin-dependent diabetes mellitus, hyperglycemia, or obesity. 
     
     
         3 . The method of  claim 1 , wherein the carboxy-terminal heterologous moiety comprises all or a portion of an albumin protein, or all or a portion of an immunoglobulin constant region, or polyethylene glycol. 
     
     
         4 . The method of  claim 3 , wherein the immunoglobulin constant region is a carboxy-terminal immunoglobulin G Fc domain. 
     
     
         5 . The method of  claim 4 , wherein the carboxy-terminal immunoglobulin G Fc domain comprises an amino acid sequence that is SEQ ID NO: 17, SEQ ID NO: 21, or a functional fragment thereof. 
     
     
         6 . The method of  claim 1 , wherein the amino-terminal region and the carboxy-terminal heterologous moiety are separated by a linker region. 
     
     
         7 . The method of  claim 6 , wherein the linker region comprises 22 amino acids in length. 
     
     
         8 . The method of  claim 6 , wherein the linker region comprises an amino acid sequence that is SEQ ID NO: 18, or a functional fragment thereof 
     
     
         9 . The method of  claim 1 , wherein the carboxy-terminal heterologous moiety is fused at or between amino acids in the fusion polypeptide corresponding to 165 to 175 of the amino-terminal region. 
     
     
         10 . The method of  claim 1 , wherein the fusion polypeptide lacks a glycosylphosphatidylinositol (GPI) domain. 
     
     
         11 . The method of  claim 1 , wherein the fusion polypeptide further comprises a functional signal domain for secretion. 
     
     
         12 . The method of  claim 1 , wherein the amino acid sequence of the amino-terminal region comprises SEQ ID NO: 20. 
     
     
         13 . The method of  claim 1 , wherein the amino acid sequence of the amino-terminal region is SEQ ID NO: 20. 
     
     
         14 . The method of  claim 1 , wherein the amino acid sequence of the amino-terminal region further comprises a signal peptide for secretion. 
     
     
         15 . The method of  claim 14 , wherein the amino acid sequence of the amino-terminal region and the signal peptide for secretion comprises SEQ ID NO: 19. 
     
     
         16 . The method of  claim 14 , wherein the amino acid sequence of the amino-terminal region and the signal peptide for secretion is SEQ ID NO: 19. 
     
     
         17 . The method of  claim 1 , wherein the amino acid sequence of the fusion polypeptide comprises SEQ ID NO: 10. 
     
     
         18 . The method of  claim 1 , wherein the amino acid sequence of the fusion polypeptide is SEQ ID NO: 10. 
     
     
         19 . The method of  claim 1 , wherein the fusion polypeptide is administered to the subject intravenously or subcutaneously. 
     
     
         20 . The method of  claim 1 , wherein the subject is a human.