The Cancer Mutation D83V Induces an α-Helix to β-Strand Conformation Switch in MEF2B. Issue 8 (13th April 2018)

• Record Type: Journal Article
• Authors: Lei, Xiao; Kou, Yi; Fu, Yang; Rajashekar, Niroop; Shi, Haoran; Wu, Fang; Xu, Jiang; Luo, Yibing; Chen, Lin
• Is Part Of: Journal of molecular biology. Volume 430:Issue 8(2018)
• Page Start: 1157
• Page End: 1172
• Publication Date: 2018-04-13
• Subjects: MEF2 myocyte enhancer factor 2 -- DLBCL diffuse large B-cell lymphoma -- WT wild-type -- DLS dynamic light scattering -- MALS multi-angle light scattering -- EMSA electrophoresis mobility shift assay; cancer mutation -- lymphoma -- MEF2B -- protein conformation change -- metamorphic protein structure; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2018.02.012
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: MEF2B is a major target of somatic mutations in non-Hodgkin lymphoma. Most of these mutations are non-synonymous substitutions of surface residues in the MADS-box/MEF2 domain. Among them, D83V is the most frequent mutation found in tumor cells. The link between this hotspot mutation and cancer is not well understood. Here we show that the D83V mutation induces a dramatic α-helix to β-strand switch in the MEF2 domain. Located in an α-helix region rich in β-branched residues, the D83V mutation not only removes the extensive helix stabilization interactions but also introduces an additional β-branched residue that further shifts the conformation equilibrium from α-helix to β-strand. Cross-database analyses of cancer mutations and chameleon sequences revealed a number of well-known cancer targets harboring β-strand favoring mutations in chameleon α-helices, suggesting a commonality of such conformational switch in certain cancers and a new factor to consider when stratifying the rapidly expanding cancer mutation data. Graphical abstract: Highlights: D83V is the most frequent mutation of MEF2B found in non-Hodgkin lymphoma DLBCL; The D83V mutation induces an α-helix to β-strand switch in the MEF2 domain; The structural change is predicted to alter the functions of MEF2; The hotspot mutation shifts the conformation of a discordant α-helix to β-strand; Other cancer mutations may use a similar mechanism to change protein function.