Abstract:
:Crystallographic structures indicate that gamma-chain residue Asn308 participates in D:D interactions and indeed substitutions of gammaAsn308 with lysine or isoleucine have been identified in dysfibrinogens with impaired polymerization. To probe the role of Asn308 in polymerization, we synthesized 3 variant fibrinogens: gammaAsn308 changed to lysine (gammaN308K), isoleucine (gammaN308I), and alanine (gammaN308A). We measured thrombin-catalyzed polymerization by turbidity, fibrinopeptide release by high-performance liquid chromatography, and factor XIIIa-catalyzed cross-linking by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In the absence of added calcium, polymerization was clearly impaired with all 3 variants. In contrast, at 0.1 mM calcium, only polymerization of gammaN308K remained markedly abnormal. The release of thrombin-catalyzed fibrinopeptide B (FpB) was delayed in the absence of calcium, whereas at 1 mM calcium FpB release was delayed only with gammaN308K. Factor XIIIa-catalyzed gamma-gamma dimer formation was delayed with fibrinogen (in absence of thrombin), whereas with fibrin (in presence of thrombin) gamma-gamma dimer formation of only gammaN308K was delayed. These data corroborate the recognized link between FpB release and polymerization. They show fibrin cross-link formation likely depends on the structure of protofibrils. Together, our results show substitution of Asn308 with a hydrophobic residue altered neither polymer formation nor polymer structure at physiologic calcium concentrations, whereas substitution with lysine altered both.
journal_name
Bloodjournal_title
Bloodauthors
Okumura N,Gorkun OV,Terasawa F,Lord STdoi
10.1182/blood-2003-12-4296subject
Has Abstractpub_date
2004-06-01 00:00:00pages
4157-63issue
11eissn
0006-4971issn
1528-0020pii
2003-12-4296journal_volume
103pub_type
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