Protein residue network analysis reveals fundamental properties of the human coagulation factor VIII

Hemophilia A is an X-linked inherited blood coagulation disorder caused by the production and circulation of defective coagulation factor VIII protein. People living with this condition receive either prophylaxis or on-demand treatment, and approximately 30% of patients develop inhibitor antibodies,...

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Bibliographic Details
Published inScientific reports Vol. 11; no. 1; pp. 12625 - 11
Main Authors Lopes, Tiago J. S., Rios, Ricardo, Nogueira, Tatiane, Mello, Rodrigo F.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 16.06.2021
Nature Publishing Group
Nature Portfolio
Subjects
631/114/1305
631/114/2408
631/114/663
631/45/612/1221
692/699/1541
Amino acids
Biological properties
Blood coagulation
Coagulation
Coagulation factor VIII
Coagulation factors
Factor VIII deficiency
Hemophilia
Humanities and Social Sciences
multidisciplinary
Prophylaxis
Protein structure
Proteins
Residues
Science
Science (multidisciplinary)
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Summary:Hemophilia A is an X-linked inherited blood coagulation disorder caused by the production and circulation of defective coagulation factor VIII protein. People living with this condition receive either prophylaxis or on-demand treatment, and approximately 30% of patients develop inhibitor antibodies, a serious complication that limits treatment options. Although previous studies performed targeted mutations to identify important residues of FVIII, a detailed understanding of the role of each amino acid and their neighboring residues is still lacking. Here, we addressed this issue by creating a residue interaction network (RIN) where the nodes are the FVIII residues, and two nodes are connected if their corresponding residues are in close proximity in the FVIII protein structure. We studied the characteristics of all residues in this network and found important properties related to disease severity, interaction to other proteins and structural stability. Importantly, we found that the RIN-derived properties were in close agreement with in vitro and clinical reports, corroborating the observation that the patterns derived from this detailed map of the FVIII protein architecture accurately capture the biological properties of FVIII.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-021-92201-3