6MFQ

Crystal structure of a PMS2 variant

6MFQ の概要

• エントリーDOI: 10.2210/pdb6mfq/pdb
• 分子名称: Mismatch repair endonuclease PMS2 (2 entities in total)
• 機能のキーワード: mismatch repair, variant of uncertain significance, atpase domain, hydrolase, dna repair enzyme
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 81997.53

構造登録者

D'Arcy, B.M.,Prakash, A. (登録日: 2018-09-11, 公開日: 2019-02-06, 最終更新日: 2023-10-11)

主引用文献

D'Arcy, B.M.,Blount, J.,Prakash, A.
Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene.
Hum. Mutat., 40:458-471, 2019

PubMed Abstract: Lynch syndrome (LS) is an autosomal dominant inherited disorder that is associated with an increased predisposition to certain cancers caused by loss-of-function mutations in one of four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2). The diagnosis of LS is often challenged by the identification of missense mutations where the functional effects are not known. These are termed variants of uncertain significance (VUSs) and account for 20%-30% of noncoding and missense mutations. VUSs cause ambiguity during clinical diagnosis and hinder implementation of appropriate medical management. In the current study, we focus on the functional and biological consequences of two nonsynonymous VUSs in PMS2. These variants, c.620G>A and c.123_131delGTTAGTAGA, result in the alteration of glycine 207 to glutamate (p.Gly207Glu) and the deletion of amino acid residues 42-44 (p.Leu42_Glu44del), respectively. While the PMS2 p.Gly207Glu variant retains in vitro MMR and ATPase activities, PMS2 p.Leu42_Glu44del appears to lack such capabilities. Structural and biophysical characterization using circular dichroism, small-angle X-ray scattering, and X-ray crystallography of the N-terminal domain of the PMS2 variants indicate that the p.Gly207Glu variant is properly folded similar to the wild-type enzyme, whereas p.Leu42_Glu44del is disordered and prone to aggregation.

PubMed: 30653781
DOI: 10.1002/humu.23708

実験手法

X-RAY DIFFRACTION (2.6 Å)