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Structural basis for type-I and type-II deficiencies of antithrombotic plasma protein-C - patterns revealed by 3-dimensional molecular modeling of mutations of the protease domain

Academic Article
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Overview

authors

  • Greengard, J. S.
  • Fisher, C. L.
  • Villoutreix, B.
  • Griffin, John

publication date

  • April 1994

journal

  • Proteins-Structure Function and Genetics  Journal

abstract

  • 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.

subject areas

  • Amino Acid Sequence
  • Binding Sites
  • Blood Coagulation Disorders
  • Enzyme Activation
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Peptide Fragments
  • Phenotype
  • Proline
  • Protein C
  • Protein C Deficiency
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Serine Endopeptidases
  • Structure-Activity Relationship
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Research

keywords

  • ACTIVATION PEPTIDE
  • BETA-BARREL DISRUPTION
  • EXOSITE
  • GENETIC DISEASE
  • HOMOLOGY MODEL
  • MUTATION DATABASE
  • SERINE PROTEASE
  • STRUCTURE FUNCTION
  • THROMBOPHILIA
  • THROMBOSIS
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Identity

International Standard Serial Number (ISSN)

  • 0887-3585

Digital Object Identifier (DOI)

  • 10.1002/prot.340180407

PubMed ID

  • 8208728
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Additional Document Info

start page

  • 367

end page

  • 380

volume

  • 18

issue

  • 4

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