Protein C Sapporo (protein C Glu 25 → Lys): A heterozygous missense mutation in the Gla domain provides new insight into the interaction between protein C and endothelial protein C receptor

Toru Nakabayashi, Kazuhiro Mizukami, Sumiyoshi Naitoh, Mika Takeda, Yasuo Shikamoto, Takafumi Nakagawa, Hiroki Kaneko, Takashi Tarumi, Itaru Mizoguchi, Hiroshi Mizuno, Masahiro Ieko, Takao Koike

研究成果: Article

6 被引用数 (Scopus)

抄録

Interaction of the γ-carboxyglutamic acid (Gla) domain of protein C with endothelial protein C receptor (EPCR) is a critical step for efficient activation of protein C, though interactions by mutants in the Gla domain of protein C with EPCR have been rarely evaluated. We identified a 44-year-old Japanese woman with a history of recurrent thromboembolism as an inherited missense mutation, the first such case reported in Japan, which involved a protein C Gla 25 mutation.Total protein C antigen and Gla protein C antigen levels in the proband were normal. Protein C activity measured with an anticoagulant assay was reduced, whereas that measured with an amidolytic assay was normal. She was therefore phenotypically diagnosed as type IIb protein C deficiency. Direct sequencing of the PCR fragments revealed a heterozygous G to A transition at nucleotide position 1462 in exon 3, which predicted an amino acid substitution of Glu 25 by Lys. Her mother and one son were also heterozygous for this mutation. A molecular dynamics simulation of Gla 25→Lys/EPCR complex in water suggested that the affinity between the molecules was decreased compared to the wild type Gla domain/EPCR complex. Since Gla 25 has been shown to play an important role in protein C function, not only in membrane phospholipid binding but also in bindingto EPCR,our findings provide new insight into the mechanism by which the Glu 25→4Lys mutation induces type IIb protein C deficiency in individuals.

本文言語English
ページ(範囲)942-950
ページ数9
ジャーナルThrombosis and Haemostasis
94
5
DOI
出版ステータスPublished - 2005 11 1
外部発表はい

ASJC Scopus subject areas

  • Hematology

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