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Identification and computationally‐based structural interpretation of naturally occurring variants of human protein C
Author(s) -
Rovida Ermanna,
Merati Giuliana,
D'Ursi Pasqualina,
Zanardelli Sara,
Marino Francesca,
Fontana Gessica,
Castaman Giancarlo,
Faioni Elena M.
Publication year - 2007
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20445
Subject(s) - biology , computational biology , recombinant dna , gene , hum , genetics , art , performance art , art history
Protein C (PC) is a key regulator of blood clotting and inflammation. Its inherited deficiency is associated with venous thromboembolism, and recombinant activated PC is currently used to increase survival in severe sepsis. The molecular basis of inherited PC deficiency is heterogeneous. Due to its multiple physiologic interactions and functions, and its modular structure, natural variants aid in the understanding of the relationship between critical residues and discrete functions. This knowledge has important therapeutic implications in the planning of a recombinant activated PC with a specific therapeutic target and devoid of major collateral effects. A way of predicting important functional consequences of residue variation is the use of molecular modeling and structural interpretation of amino acidic substitutions. A study of 21 out of 32 identified PC gene (PROC) variants is presented. For three of them, localized in the active site, electrostatic potential variation was calculated. For more than half of the studied variants, an explanation for the functional impairment could be derived from computational analysis, allowing a focused choice of which variants it is worthwhile pursuing. Hum Mutat 28(4), 345–355, 2007. © 2006 Wiley‐Liss, Inc.