Evolutionary conserved rigid module-domain interactions can be detected at the sequence level: the examples of complement and blood coagulation proteases.
Several extracellular modular proteins, including proteases of the complement and blood coagulation cascades, are shown here to exhibit conserved sequence patterns specific for a particular module-domain association. This was detected by comparative analysis of sequence variability in different multiple sequence alignments, which provides a new tool to investigate the evolution of modular proteins. A first example deals with the proteins featuring a common complement control protein (CCP) module-serine protease (SP) domain pattern at their C-terminal end, defined here as the CCP-SP sub-family. These proteins include the complement proteases C1r, C1s and MASPs, the Limulus clotting factor C, and the proteins of the haptoglobin family. A second example deals with blood coagulation factors VII, IX and X and protein C, all featuring a common epidermal growth factor (EGF)-SP C-terminal assembly. Highly specific motifs are found at the connection between the CCP or EGF module and the activation peptide of the SP domain: [P/A]-x-C-x-[P/A]-[I/V]-C-G-x-[P/S/K] in the case of the CCP-SP proteins, and C-x-[P/S]-x-x-x-[Y/F]-P-C-G in the case of the EGF-SP proteins. Each motif is strictly conserved in the whole sub-family and it is detected in no more than one other known protein sequence. Strikingly, most of the conserved residues specific to each sub-family appear to be clustered at the interface between the SP domain and the CCP or EGF module. We propose that a rigid module-domain interaction occurs in these proteins and has been conserved through evolution. The functional implications of these assemblies, underlined by such evolutionary constraints, are discussed.
Gaboriaud
C
C
Laboratoire de Cristallogenèse et Cristallographie des Protéines. Institut de Biologie Structuralel, 38027 Grenoble Cedex 1, France. chris@ccp.ibs.fr
Rossi
V
V
Fontecilla-Camps
J C
JC
Arlaud
G J
GJ
D000595:Amino Acid Sequence; D000818:Animals; D001779:Blood Coagulation Factors / Q000737:chemistry*; D003165:Complement System Proteins / Q000737:chemistry*; D017124:Conserved Sequence; D004285:Dogs; D019143:Evolution, Molecular; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D051381:Rats; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000097:blood* / Q000737:chemistry*
D001779:Blood Coagulation Factors; D003165:Complement System Proteins; D012697:Serine Endopeptidases