title: Identification and computationally-based structural interpretation of naturally occurring variants of human protein C.
abstract: 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.
authors.affiliation: Institute of Biomedical Technologies-National Research Council, Segrate, Milano, Italy. ermanna.rovida@itb.cnr.it
authors.forename: Ermanna
authors.initials: E
authors.lastname: Rovida
authors.forename: Giuliana
authors.initials: G
authors.lastname: Merati
authors.forename: Pasqualina
authors.initials: P
authors.lastname: D'Ursi
authors.forename: Sara
authors.initials: S
authors.lastname: Zanardelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Marino
authors.forename: Gessica
authors.initials: G
authors.lastname: Fontana
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Castaman
authors.forename: Elena M
authors.initials: EM
authors.lastname: Faioni
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011486:Protein C / Q000737:chemistry* / Q000235:genetics*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: D011486:Protein C