Molecular dynamics characterization of five pathogenic factor X mutants associated with decreased catalytic activity

Raimondo De Cristofaro, Safwat Abdel-Azeim, Romina Oliva, Edrisse Chermak, Luigi Cavallo

Risultato della ricerca: Contributo in rivistaArticolo in rivista

12 Citazioni (Scopus)

Abstract

Factor X (FX) is one of the major players in the blood coagulation cascade. Upon activation to FXa, it converts prothrombin to thrombin, which in turn converts fibrinogen into fibrin (blood clots). FXa deficiency causes hemostasis defects, such as intracranial bleeding, hemathrosis, and gastrointestinal blood loss. Herein, we have analyzed a pool of pathogenic mutations, located in the FXa catalytic domain and directly associated with defects in enzyme catalytic activity. Using chymotrypsinogen numbering, they correspond to D102N, T135M, V160A, G184S, and G197D. Molecular dynamics simulations were performed for 1.68 μs on the wild-type and mutated forms of FXa. Overall, our analysis shows that four of the five mutants considered, D102N, T135M, V160A, and G184S, have rigidities higher than those of the wild type, in terms of both overall protein motion and, specifically, subpocket S4 flexibility, while S1 is rather insensitive to the mutation. This acquired rigidity can clearly impact the substrate recognition of the mutants.
Lingua originaleEnglish
pagine (da-a)6992-7001
Numero di pagine10
RivistaBiochemistry
Volume53
DOI
Stato di pubblicazionePubblicato - 2014

Keywords

  • Biocatalysis
  • Biochemistry
  • Catalytic Domain
  • Factor X
  • Humans
  • Hydrogen Bonding
  • Molecular Dynamics Simulation
  • Mutation, Missense
  • Principal Component Analysis
  • Protein Structure, Secondary
  • Thermodynamics

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