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Why alpha-antiplasmin must be converted to a derivative form for optimal function.
K N Lee1, K W Jackson, V J Christiansen
1William K. Warren Medical Research Center and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA. kyung-lee@ouhsc.edu
Journal of Thrombosis and Haemostasis : JTH
|September 22, 2007
Summary
Human alpha(2)-antiplasmin (alpha(2)AP) crosslinking to fibrin is significantly enhanced when the N-terminal peptide is cleaved, yielding Asn-alpha(2)AP. This process, however, is slowed by the R6W polymorphism, impacting fibrinolysis regulation.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Human alpha(2)-antiplasmin (alpha(2)AP) is the primary inhibitor of fibrinolysis, circulating as a 464-residue protein with a Met N-terminus.
- A known R6W polymorphism in alpha(2)AP has been implicated in affecting fibrinolytic rates.
- Antiplasmin-cleaving enzyme (APCE) cleaves Met-alpha(2)AP at the Pro12-Asn13 bond, producing Asn-alpha(2)AP.
Purpose of the Study:
- To compare the crosslinking efficiency of Met-alpha(2)AP (both R6 and W6 variants) and Asn-alpha(2)AP with fibrin.
- To evaluate the ability of these alpha(2)AP forms to protect fibrin from plasmin-mediated digestion.
- To investigate the role of the N-terminal peptide and the R6W polymorphism in alpha(2)AP crosslinking and function.
Main Methods:
- Comparative analysis of crosslinking rates using different alpha(2)AP forms (Met-alpha(2)AP(R6), Met-alpha(2)AP(W6), Asn-alpha(2)AP) with fibrin.
- Assessment of fibrin protection against plasmin digestion by various alpha(2)AP forms.
- Edman sequencing and mass spectrometry to identify crosslinking sites and analyze tryptic peptides.
Main Results:
- Asn-alpha(2)AP exhibits approximately twelvefold faster crosslinking to fibrin via Gln14 compared to Met-alpha(2)AP variants, enhancing fibrin's resistance to plasmin.
- All three alpha(2)AP forms inhibit plasmin at identical rates.
- The N-terminal 12-residue peptide of Met-alpha(2)AP hinders factor XIIIa access to Gln14, slowing crosslinking; Gln14 is identified as the primary crosslinking site.
Conclusions:
- Cleavage of the N-terminal peptide yields Asn-alpha(2)AP, which rapidly crosslinks to fibrin, providing maximal protection against plasmin.
- The R6W polymorphism does not alter alpha(2)AP's intrinsic fibrin crosslinking ability but slows APCE cleavage, reducing available Asn-alpha(2)AP for rapid fibrin crosslinking.
- The N-terminal peptide's structure significantly influences the rate of fibrin crosslinking and subsequent fibrinolysis regulation.
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