Structural basis for type I and type II deficiencies of antithrombotic plasma protein C: Patterns revealed by three-dimensional molecular modelling of mutations of the protease domain
| Autor: | Cindy L. Fisher, John H. Griffin, Judith S. Greengard, Bruno O. Villoutreix |
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| Rok vydání: | 1994 |
| Předmět: |
Models
Molecular Proline medicine.medical_treatment Molecular Sequence Data Biochemistry Structure-Activity Relationship Protein structure Structural Biology medicine Humans Missense mutation Amino Acid Sequence Homology modeling Binding site Molecular Biology Peptide sequence Serine protease Genetics Binding Sites Protease Sequence Homology Amino Acid biology Serine Endopeptidases Protein C Deficiency Active site Blood Coagulation Disorders Peptide Fragments Protein Structure Tertiary Enzyme Activation Phenotype Mutation biology.protein Protein C |
| Zdroj: | Proteins: Structure, Function, and Genetics. 18:367-380 |
| ISSN: | 1097-0134 0887-3585 |
| DOI: | 10.1002/prot.340180407 |
| Popis: | Familial deficiency of protein C is associated with inherited thrombophilia. To explore how specific missense mutations might cause observed clinical phenotypes, know protein C missense mutations were mapped onto three-dimensional homology models of the protein C protease domain, and the implications for domain folding and structure were evaluated. Most Type I missense mutations either replaced internal hydrophobic residues (I201T, L223F, A259V, A267T, A346T, A346V, G376D) or nearby interacting residues (I403M, T298M, Q184H), thus disrupting the packing of internal hydrophobic side chains, or changed hydrophilic residues, thus disrupting ion pairs (N256D, R178W). Mutations (P168L, R169W) at the activation site destabilized the region containing the activation peptide structure. Most Type II mutations involved solvent-exposed residues and were clustered either in a positively charged region (R147W, R157Q, R229Q, R352W) or were located in or near the active site region (S252N, D359N, G381S, G391S, H211Q). The cluster of arginines 147, 157, 229, and 352 may identify a functionally important exosite. Identification of the spatial relationships of natural mutations in the protein C model is helpful for understanding manifestations of protein C deficiency and for identification of novel, functionally important molecular features and exosites. |
| Databáze: | OpenAIRE |
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