Structural highlights
Disease
FIBA_HUMAN Defects in FGA are a cause of congenital afibrinogenemia (CAFBN) [MIM:202400. This is a rare autosomal recessive disorder characterized by bleeding that varies from mild to severe and by complete absence or extremely low levels of plasma and platelet fibrinogen. Note=The majority of cases of afibrinogenemia are due to truncating mutations. Variations in position Arg-35 (the site of cleavage of fibrinopeptide a by thrombin) leads to alpha-dysfibrinogenemias. Defects in FGA are a cause of amyloidosis type 8 (AMYL8) [MIM:105200; also known as systemic non-neuropathic amyloidosis or Ostertag-type amyloidosis. AMYL8 is a hereditary generalized amyloidosis due to deposition of apolipoprotein A1, fibrinogen and lysozyme amyloids. Viscera are particularly affected. There is no involvement of the nervous system. Clinical features include renal amyloidosis resulting in nephrotic syndrome, arterial hypertension, hepatosplenomegaly, cholestasis, petechial skin rash.[1]
Function
FIBA_HUMAN Fibrinogen has a double function: yielding monomers that polymerize into fibrin and acting as a cofactor in platelet aggregation.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Fibrin polymerization is supported in part by interactions called "A:a". Crystallographic studies revealed gamma364Asp is part of hole "a" that interacts with knob "A" peptide mimic, GPRP. Biochemical studies have shown gamma364Asp is critical to polymerization, as polymerization of variants gammaD364A, gammaD364H, and gammaD364V is exceptionally impaired. To understand the molecular basis for the aberrant function, we solved the crystal structure of fragment D from gammaD364A. Surprisingly, the structure (rfD-gammaD364A+GP) showed near normal "A:a" interactions with GPRP bound to hole "a" and no change in the overall structure of gammaD364A. Of note, inspection of the structure showed negative electrostatic potential inside hole "a" was diminished by this substitution. We examined GPRP binding to the gamma364Asp variants in solution by plasmin protection assay. We found no protection of either gammaD364H or gammaD364V but partial protection of gammaD364A, indicating the peptide does not bind to either gammaD364H or gammaD364V and binds more weakly than normal to gammaD364A. We also examined protection by calcium and found all variants were indistinguishable from normal, suggesting the global structures of the variants are not markedly different from normal. Our data imply that gamma364Asp per se is not required for knob "A" binding to hole "a"; rather, this residue's negative charge has a critical role in the electrostatic interactions that facilitate the important first step in fibrin polymerization.
Polymerization-defective fibrinogen variant gammaD364A binds knob "A" peptide mimic.,Bowley SR, Merenbloom BK, Okumura N, Betts L, Heroux A, Gorkun OV, Lord ST Biochemistry. 2008 Aug 19;47(33):8607-13. Epub 2008 Jul 22. PMID:18642883[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Benson MD, Liepnieks J, Uemichi T, Wheeler G, Correa R. Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain. Nat Genet. 1993 Mar;3(3):252-5. PMID:8097946 doi:http://dx.doi.org/10.1038/ng0393-252
- ↑ Bowley SR, Merenbloom BK, Okumura N, Betts L, Heroux A, Gorkun OV, Lord ST. Polymerization-defective fibrinogen variant gammaD364A binds knob "A" peptide mimic. Biochemistry. 2008 Aug 19;47(33):8607-13. Epub 2008 Jul 22. PMID:18642883 doi:10.1021/bi8000769
