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001-es BibID:	BIBFORM043326
035-os BibID:	PMID:16867987
Első szerző:	Preston, Roger J. S.
Cím:	Multifunctional specificity of the protein C/activated protein C Gla domain / Roger J. S. Preston, Eva Ajzner, Cristina Razzari, Stalo Karageorgi, Sonia Dua, Björn Dahlbäck, David A. Lane
Dátum:	2006
ISSN:	0021-9258 1083-351X
Megjegyzések:	Activated protein C (APC) has potent anticoagulant and anti-inflammatory properties that are mediated in part by its interactions with its cofactor protein S and the endothelial cell protein C receptor (EPCR). The protein C/APC Gla domain is implicated in both interactions. We sought to identify how the protein C Gla domain enables specific protein-protein interactions in addition to its conserved role in phospholipid binding. The human prothrombin Gla domain, which cannot bind EPCR or support protein S cofactor activity, has 22/45 residues that are not shared with the human protein C Gla domain. We hypothesized that the unique protein C/APC Gla domain residues were responsible for mediating the specific interactions. To assess this, we generated 13 recombinant protein C/APC variants incorporating the prothrombin residue substitutions. Despite anticoagulant activity similar to wild-type APC in the absence of protein S, APC variants APC(PT33-39) (N33S/V34S/D35T/D36A/L38D/A39V) and APC(PT36/38/39) (D36A/L38D/A39V) were not stimulated by protein S, whereas APC(PT35/36) (D35T/D36A) exhibited reduced protein S sensitivity. Moreover, PC(PT8/10) (L8V/H10K) displayed negligible EPCR affinity, despite normal binding to anionic phospholipid vesicles and factor Va proteolysis in the presence and absence of protein S. A single residue variant, PC(PT8), also failed to bind EPCR. Factor VIIa, which also possesses Leu-8, bound soluble EPCR with similar affinity to wild-type protein C, collectively confirming Leu-8 as the critical residue for EPCR recognition. These results reveal the specific Gla domain residues responsible for mediating protein C/APC molecular recognition with both its cofactor and receptor and further illustrate the multifunctional potential of Gla domains.
Tárgyszavak:	Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Journal of Biological Chemistry. - 281 : 39 (2006), p. 28850-28857. -
További szerzők:	Ajzner Éva (1968-) (laboratóriumi szakorvos) Razzari, Cristina Karageorgi, Stalo Dua, Sonia Dahlbäck, Björn Lane, David A.
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat
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