Structural examination of the influence of phosphorylation on the binding of fibrinopeptide A to bovine thrombin

Biochemistry
M C MaurerH A Scheraga

Abstract

Upon addition of thrombin, fibrinopeptides A and B are cleaved off from the N-termini of four chains of fibrinogen (Aalpha Bbeta gamma)2, and sites of polymerization are exposed, resulting in formation of a fibrin clot. For the fibrinogen Aalpha chain, cleavage occurs most prevalently at the Arg16-Gly17 peptide bond. About 25-30% of the human fibrinogen Aalpha chains are phosphorylated in nature at the position of Ser3, but the function for this modification is not understood. Previous NMR studies indicated that the N-terminal portion (1ADSGE5) of unphosphorylated fibrinopeptide A does not interact with the surface of bovine thrombin. Kinetic and NMR studies have now been carried out to assess whether phosphorylation at Ser3 allows the N-terminal segment (1ADSGEGDFLAEGGGVR16) to become anchored on the thrombin surface, leading to formation of a catalytically more efficient enzyme-substrate complex. Kinetic results indicate that phosphorylation leads to an approximately 65% increase in substrate specificity (kcat/Km) toward hydrolysis of fibrinogen Aalpha(1-20). 31P NMR studies reveal that the phosphorylated group does interact with thrombin, and 1H line broadening studies suggest that phosphorylation does promote binding of ami...Continue Reading

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Citations

Aug 2, 2008·Analytical and Bioanalytical Chemistry·Claudia CirulliAngela Amoresano
Jun 25, 2010·Chemical Communications : Chem Comm·Cheng-Tai Chen, Yu-Chie Chen
Apr 22, 2006·PLoS Computational Biology·Eli S GrobanMatthew P Jacobson
Sep 18, 2002·Archives of Biochemistry and Biophysics·Anca MarinescuMuriel C Maurer
Feb 12, 2005·Journal of Mass Spectrometry : JMS·Xianglin Yuan, Dominic M Desiderio
Sep 1, 2011·Mass Spectrometry Reviews·Peihong ZhuJohn G Marshall
Dec 31, 2010·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Vera IgnjatovicPaul Monagle
Mar 20, 2002·The Journal of Biological Chemistry·Thierry Rose, Enrico Di Cera
Jul 20, 2001·Annals of the New York Academy of Sciences·A H Henschen-Edman
Sep 11, 2010·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Roman KotlínJan E Dyr

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