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A molecular dynamics approach on the Y393C variant of protein disulfide isomerase A1
Author(s) -
MaderoAyala Pablo A.,
MaresAlejandre Rosa E.,
RamosIbarra Marco A.
Publication year - 2020
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13700
Subject(s) - protein disulfide isomerase , isomerase , endoplasmic reticulum , protein folding , biochemistry , biology , oxidoreductase , gene , chaperone (clinical) , chemistry , enzyme , medicine , pathology
Abstract Human protein disulfide isomerase A1 (PDIA1) shows both catalytic (i.e., oxidoreductase) and non‐catalytic (i.e., chaperone) activities and plays a crucial role in the oxidative folding of proteins within the endoplasmic reticulum. PDIA1 dysregulation is a common trait in numerous pathophysiological conditions, including neurodegenerative disorders and cancerous diseases. The 1178A>G mutation of the human PDIA1‐encoding gene is a non‐synonymous single nucleotide polymorphism detected in patients with Cole‐Carpenter syndrome type 1 (CSS1), a particularly rare bone disease. In vitro studies showed that the encoded variant (PDIA1 Y393C) exhibits limited oxidoreductase activity. To gain knowledge on the structure–function relationship, we undertook a molecular dynamics (MD) approach to examine the structural stability of PDIA1 Y393C. Results showed that significant conformational changes are the structural consequence of the amino acid substitution Tyr>Cys at position 393 of the PDIA1 protein. This structure‐based study provides further knowledge about the molecular origin of CCS1.