التفاصيل البيبلوغرافية
| العنوان: |
Unique surface-exposed hydrophobic residues in the C1 domain of Factor VIII contribute to cofactor function and Von Willebrand Factor binding |
| المؤلفون: |
Przeradzka, Małgorzata A, Freato, Nadia, Boon-Spijker, Mariëtte, van Galen, Josse, van der Zwaan, Carmen, Mertens, Koen, van den Biggelaar, Maartje, Meijer, Alexander B |
| المساهمون: |
Afd Pharmaceutics, Afd Biomol.Mass Spect. and Proteomics, Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics |
| سنة النشر: |
2020 |
| مصطلحات موضوعية: |
actor VIII, factor IXa, kinetics, surface plasmon resonance, Von Willebrand factor, Taverne |
| الوصف: |
BACKGROUND: The identity of the amino acid regions of factor VIII (FVIII) that contribute to factor IXa (FIXa) and Von Willebrand Factor (VWF) binding has not been fully resolved. Previously, we observed that replacing the FVIII C1 domain for the one of factor V (FV) markedly reduces VWF binding and cofactor function. Compared to the FV C1 domain, this implies that the FVIII C1 domain comprises unique surface-exposed elements involved in VWF and FIXa interaction. OBJECTIVE: The aim of this study is to identify residues in the FVIII C1 domain that contribute to VWF and FIXa binding. METHODS: Structures and primary sequences of FVIII and FV were compared to identify surface-exposed residues unique to the FVIII C1 domain. The identified residues were replaced into alanine residues to identify their role in FIXa and VWF interaction. This role was assessed employing surface plasmon resonance analysis studies and enzyme kinetic assays. RESULTS: Five surface-exposed hydrophobic residues unique to the FVIII C1 domain, i.e.: F2035, F2068, F2127, V2130, I2139 were identified. Functional analysis indicated that residues F2068, V2130 and especially F2127 contribute to VWF and/or FIXa interaction. Substitution into alanine of the also surface-exposed V2125, which is spatially next to F2127, affected only VWF binding. CONCLUSION: The surface-exposed hydrophobic residues in C1 domain contribute to cofactor function and VWF binding. These findings provide novel information on the fundamental role of the C1 domain in FVIII life-cycle. |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
English |
| تدمد: |
1538-7933 |
| العلاقة: |
https://dspace.library.uu.nl/handle/1874/394343Test |
| الإتاحة: |
https://dspace.library.uu.nl/handle/1874/394343Test |
| حقوق: |
info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: |
edsbas.591D831B |
| قاعدة البيانات: |
BASE |
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