Cash (caspase homologue) with death effector domain, modulators of the function of FAS receptors

Abstract

Proteins capable of modulating or mediating the function of MORT-1 are disclosed. Also disclosed are DNA sequences encoding these proteins, the recombinant production of these proteins as well as their use.

What is claimed is:  
     
         1 . A molecule comprising a DNA sequence encoding a polypeptide which is capable of binding to one or more of MORT-1, MACH and MORT-1 binding protein Mch4, which polypeptide has the amino acid sequence of: 
 (a) a G1 protein isoform whose sequence is that of SEQ ID NO:2 or 4;    (b) a fragment of (a) which is capable of binding to one or more of MORT-1, MACH, and MORT-1 binding protein Mch4;    (c) an analog of (a) which differs from the sequence of (a) by no more than ten changes in the amino acid sequence of (a), each said change being a substitution, deletion and/or insertion of a single amino acid, which analog is capable of binding to one or more of MORT-1, MACH and MORT-1 binding protein Mch4; or    (d) a derivative of (a), (b) or (c) by modification of a functional group which occurs as a side chain or an N- or C-terminal group of one or more amino acid residues thereof without changing one amino acid to another of the twenty commonly occurring natural amino acids, which derivative is capable of binding to one or more of MORT-1, MACH, and MORT-1 binding protein Mch4.    
     
     
         2 . A molecule in accordance with  claim 1 , wherein said polypeptide has the amino acid sequence of said G1 protein isoform of SEQ ID NO:2  
     
     
         3 . A molecule in accordance with  claim 2 , wherein the DNA sequence encoding said G1 protein isoform is SEQ ID NO: 1.  
     
     
         4 . A molecule in accordance with  claim 1 , wherein said polypeptide has the amino acid sequence of said G1 protein isoform of SEQ ID NO:4  
     
     
         5 . A molecule in accordance with  claim 4 , wherein the DNA sequence encoding said G1 protein isoform is SEQ ID NO:3.  
     
     
         6 . A molecule in accordance with  claim 1 , wherein the polypeptide has the amino acid sequence of (c), which is an analog that differs from the sequence of (a) by no more than ten changes in the amino acid sequence of (a), each said change being a deletion and/or insertion of a single amino acid, which analog is capable of binding to one or more of MORT-1, MACH, and MORT-1 binding protein Mch4.  
     
     
         7 . A molecule in accordance with  claim 1 , wherein the polypeptide has the amino acid sequence of (c), which is an analog that differs from the sequence of (a) by the substitution, deletion or insertion of a single amino acid residue, which analog is capable of binding to one or more of MORT-1, MACH, and MORT-1 binding protein Mch4.  
     
     
         8 . A molecule in accordance with  claim 1 , comprising a DNA sequence encoding a G1 isoform whose sequence is that of SEQ ID NO:2 or 4, which polypeptide is capable of binding to one or more of MORT-1, MACH, and MORT-1 binding protein Mch4.  
     
     
         9 . A molecule in accordance with  claim 8 , wherein the DNA sequence encoding said G1 protein isoform is that of SEQ ID NO: 1 or SEQ ID NO:3.  
     
     
         10 . A vector comprising the molecule in accordance with  claim 8 .  
     
     
         11 . Transformed host cells containing the vector in accordance with  claim 10 .  
     
     
         12 . A method for producing a polypeptide which has the amino acid sequence of a G1 protein isoform whose sequence is that of SEQ ID NO:2 or 4, which polypeptide is capable of binding to one or more of MORT-1, MACH, and MORT-1 binding protein Mch4, comprising: 
 growing transformed host cells in accordance with  claim 11  under conditions suitable for the expression of an expression product;    effecting post-translational modifications of said expression product as necessary for obtaining said polypeptide; and    isolating said polypeptide.    
     
     
         13 . A vector comprising the molecule in accordance with  claim 1 .  
     
     
         14 . A vector in accordance with  claim 13  capable of being expressed in a eukaryotic host cell.  
     
     
         15 . A vector in accordance with  claim 13  capable of being expressed in a prokaryotic host cell.  
     
     
         16 . Transformed host cells containing the vector in accordance with  claim 13 .  
     
     
         17 . A method for producing a polypeptide which is capable of binding to one or more of MORT-1, MACH and MORT-1 binding protein Mch4, comprising: 
 growing transformed host cells in accordance with  claim 16  under conditions suitable for the expression of an expression product;    effecting post-translational modifications of said expression product as necessary for obtaining said polypeptide; and    isolating said polypeptide.    
     
     
         18 . A polypeptide which is capable of binding to one or more of MORT-1, MACH and MORT-1 binding protein Mch4, which polypeptide has the amino acid sequence of: 
 (a) a G1 protein isoform whose sequence is that of SEQ ID NO:2 or 4;    (b) a fragment of (a) which is capable of binding to one or more of MORT-1, MACH, and MORT-1 binding protein Mch4;    (c) an analog of (a) which differs from the sequence of (a) by no more than ten changes in the amino acid sequence of (a), each said change being a substitution, deletion and/or insertion of a single amino acid, which analog is capable of binding to one or more of MORT-1, MACH, and MORT-1 binding protein Mch4; or    (d) a derivative of (a), (b) or (c) by modification of a functional group which occurs as a side chain or an N- or C-terminal group of one or more amino acid residues thereof without changing one amino acid to another of the twenty commonly occurring natural amino acids, which derivative is capable of binding to one or more of MORT-1, MACH, and MORT-1 binding protein Mch4.    
     
     
         19 . A polypeptide in accordance with  claim 18 , having the amino acid sequence of the G1 protein isoform of SEQ ID NO:2.  
     
     
         20 . A polypeptide in accordance with  claim 18 , having the amino acid sequence of the G1 protein isoform of SEQ ID NO:4.  
     
     
         21 . A polypeptide in accordance with  claim 18 , having the amino acid sequence of an analog which differs from the sequence of (a) by the substitution, deletion or insertion of a single amino acid residue, which analog is capable of binding to one or more of MORT-1, MACH, and MORT-1 binding protein Mch4.  
     
     
         22 . A polypeptide in accordance with  claim 18 , which has the amino acid sequence of a G1 protein isoform whose sequence is that of SEQ ID NO:2 or 4, which polypeptide is capable of binding to one or more of MORT-1 and MACH.  
     
     
         23 . A polypeptide in accordance with  claim 18 , having the amino acid sequence of an analog which differs from the sequence of (a) by no more than ten changes in the amino acid sequence of (a), each said change being a deletion and/or insertion of a single amino acid, which analog is capable of binding to one or more of MORT-1, MACH, and MORT-1 binding protein Mch4.  
     
     
         24 . A pharmaceutical composition for the modulation of the FAS-R ligand- or TNF-effect on cells comprising, as active ingredient, the polypeptide according to  claim 18 .  
     
     
         25 . A molecule comprising a DNA sequence encoding a polypeptide which is capable of binding to one or more of MORT-1, MACH and MORT-1 binding protein Mch4, which polypeptide has the amino acid sequence of: 
 (a) a protein comprising the amino acid sequence of residues 1 to 142 of SEQ ID NO:4;    (b) a fragment of (a) which is capable of binding to one or more of MORT-1, MACH, and MORT-1 binding protein Mch4;    (c) an analog of (a) which differs from the sequence of (a) by no more than ten changes in the amino acid sequence of (a), each said change being a substitution, deletion and/or insertion of a single amino acid, which analog is capable of binding to one or more of MORT-1, MACH and MORT-1 binding protein Mch4; or    (d) a derivative of (a), (b) or (c) by modification of a functional group which occurs as a side chain or an N- or C-terminal group of one or more amino acid residues thereof without changing one amino acid to another of the twenty commonly occurring natural amino acids, which derivative is capable of binding to one or more of MORT-1, MACH, and MORT-1 binding protein Mch4.    
     
     
         26 . A polypeptide which is capable of binding to one or more of MORT-1, MACH and MORT-1 binding protein Mch4, which polypeptide has the amino acid sequence of: 
 (a) a protein comprising the amino acid sequence of residues 1 to 142 of SEQ ID NO:4;    (b) a fragment of (a) which is capable of binding to one or more of MORT-1, MACH, and MORT-1 binding protein Mch4;    (c) an analog of (a) which differs from the sequence of (a) by no more than ten changes in the amino acid sequence of (a), each said change being a substitution, deletion and/or insertion of a single amino acid, which analog is capable of binding to one or more of MORT-1, MACH, and MORT-1 binding protein Mch4; or    (d) a derivative of (a), (b) or (c) by modification of a functional group which occurs as a side chain or an N- or C-terminal group of one or more amino acid residues thereof without changing one amino acid to another of the twenty commonly occurring natural amino acids, which derivative is capable of binding to one or more of MORT-1, MACH, and MORT-1 binding protein Mch4.