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Published on: June 3, 2014
Structural interpretation of 42 mutations causing factor XI deficiency using homology modeling
N M O'Connell1, R E Saunders, C A Lee
1The Katharine Dormandy Haemophilia Center and Haemostasis Unit, The Royal Free & University College Medical School, London, UK.
Background:
Factor (F)XI is important in the consolidation phase of blood coagulation. The structural effects of mutations causing FXI deficiency have not been well described due to the lack of a structure for FXI.
Objectives:
To develop molecular models of the four apple (Ap) and serine protease (SP) domains in FXI in order to assess the structural effects of published FXI mutations in the light of their phenotypes.
Methods:
The Ap domains were modeled using the NMR structure of an adhesin from Eimeria tenella. The SP domain was modeled using the crystal structure of beta-tryptase.
Results:
The effect of 42 mutations causing FXI deficiency was analyzed using homology models for the Ap and SP domains in FXI. Protein misfolding was implicated as the likely structural mechanism of disease in six of 14 mutations in the four Ap domains with Type I phenotypes. Likewise, misfolding was implicated in eight of 14 mutations in the SP domain with Type I phenotypes. Unlike other coagulation factor deficiencies, Type II phenotypes based on a catalytically dysfunctional FXI are uncommon. The structural models indicated that two known Type II mutations in the Ap domains could be correlated with functional defects in substrate or cofactor binding, and likewise four Type II mutations in the SP domain would disrupt the active site.
Conclusions:
New FXI disease-causing mutations can now be structurally characterized to complement phenotypic data, and expression studies can be designed to verify the molecular basis of each deficiency.
Insights
Molecular models reveal that protein misfolding is a key mechanism in Factor XI (FXI) deficiency. These models help characterize new FXI mutations and understand their impact on blood coagulation.
Area of Science:
- Biochemistry
- Molecular Biology
- Hematology
Background:
- Factor XI (FXI) plays a critical role in the consolidation phase of blood coagulation.
- Structural insights into FXI mutations causing deficiency have been limited due to the absence of a defined FXI structure.
Purpose of the Study:
- To develop molecular models of the apple (Ap) and serine protease (SP) domains of FXI.
- To structurally assess the effects of published FXI mutations and correlate them with observed phenotypes.
Main Methods:
- Homology modeling was employed for the Ap domains using an NMR structure of an adhesin.
- The SP domain was modeled using the crystal structure of beta-tryptase.
Main Results:
- Analysis of 42 mutations causing FXI deficiency using homology models.
- Protein misfolding identified as a likely mechanism for Type I FXI deficiency in both Ap and SP domains.
- Structural analysis of Type II mutations suggests disruption of substrate/cofactor binding or active site integrity.
Conclusions:
- The developed molecular models enable structural characterization of novel FXI mutations.
- These models complement phenotypic data and guide the design of expression studies to elucidate molecular mechanisms of FXI deficiency.
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