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

Handle URI:
http://hdl.handle.net/10754/563850
Title:
Molecular dynamics characterization of five pathogenic factor X mutants associated with decreased catalytic activity
Authors:
Abdel-Azeim, Safwat ( 0000-0001-8611-1251 ) ; Oliva, Romina M.; Chermak, Edrisse ( 0000-0002-2716-5724 ) ; De Cristofaro, Raimondo; Cavallo, Luigi ( 0000-0002-1398-338X )
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.
KAUST Department:
KAUST Catalysis Center (KCC); Physical Sciences and Engineering (PSE) Division; Chemical Science Program
Publisher:
American Chemical Society (ACS)
Journal:
Biochemistry
Issue Date:
11-Nov-2014
DOI:
10.1021/bi500770p
PubMed ID:
25313940
Type:
Article
ISSN:
00062960
Sponsors:
Research reported in this publication was supported by the King Abdullah University of Science and Technology.
Appears in Collections:
Articles; Physical Sciences and Engineering (PSE) Division; Chemical Science Program; KAUST Catalysis Center (KCC)

Full metadata record

DC FieldValue Language
dc.contributor.authorAbdel-Azeim, Safwaten
dc.contributor.authorOliva, Romina M.en
dc.contributor.authorChermak, Edrisseen
dc.contributor.authorDe Cristofaro, Raimondoen
dc.contributor.authorCavallo, Luigien
dc.date.accessioned2015-08-03T12:16:54Zen
dc.date.available2015-08-03T12:16:54Zen
dc.date.issued2014-11-11en
dc.identifier.issn00062960en
dc.identifier.pmid25313940en
dc.identifier.doi10.1021/bi500770pen
dc.identifier.urihttp://hdl.handle.net/10754/563850en
dc.description.abstractFactor 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.en
dc.description.sponsorshipResearch reported in this publication was supported by the King Abdullah University of Science and Technology.en
dc.publisherAmerican Chemical Society (ACS)en
dc.titleMolecular dynamics characterization of five pathogenic factor X mutants associated with decreased catalytic activityen
dc.typeArticleen
dc.contributor.departmentKAUST Catalysis Center (KCC)en
dc.contributor.departmentPhysical Sciences and Engineering (PSE) Divisionen
dc.contributor.departmentChemical Science Programen
dc.identifier.journalBiochemistryen
dc.contributor.institutionDepartment of Sciences and Technologies, University Parthenope of Naples, Centro Direzionale Isola C4Naples, Italyen
dc.contributor.institutionHemostasis Research Centre, Institute of Internal Medicine and Geriatrics, Catholic University School of MedicineRome, Italyen
dc.contributor.institutionDipartimento di Chimica e Biologia, University of Salerno, Via Papa Giovanni Paolo IIFisciano, Italyen
kaust.authorAbdel-Azeim, Safwaten
kaust.authorChermak, Edrisseen
kaust.authorCavallo, Luigien

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