Exp Mol Med.  1999 Mar;31(1):47-51.

A molecular model of a point mutation (Val297Met) in the serine protease domain of protein C

• Song KS
• Park YS
• Choi JR
• Kim HK
• Park Q

Abstract

A heterozygous GTG to ATG (Val297Met) mutation was detected in a patient with inherited protein C deficiency and deep vein thrombosis. Cosegregation of the mutation with protein C deficiency was observed through a family pedigree study. Molecular models of the serine protease domains of wild type and mutant protein C were constructed by standard comparative method. Val 297 was found to be located in the hydrophobic core of the protein. Although the substitution of Met for Val does not greatly alter the hydrophobicity of the protein, it introduces a bulkier side chain, which yields steric hindrance between this residue and adjacent residues, such as Met364, Tyr393, Ile321, Ile323, and Val378. It seems that the Met can not fit into the tight packing into which it is trapped, thereby probably inducing misfolding and/or greater instability of the protein. Such misfolding and/or instability thereby eventually disturbs the catalytic triad, in consistent with the observed type I deficiency state.

Keyword

protein C deficiency; deep vein thrombosis; polymerase chain reaction (PCR); direct sequencing; point mutation; protein modeling

MeSH Terms

Adult
Base Sequence
Female
Human
Male
Middle Age
Models, Molecular*
Molecular Sequence Data
Pedigree
Point Mutation*
Polymerase Chain Reaction/methods
Protein C/genetics*
Protein C/chemistry*
Protein C Deficiency/genetics*
Protein Conformation
Serine Endopeptidases/genetics
Serine Endopeptidases/chemistry*
Venous Thrombosis/genetics