The Cancer Mutation D83V Induces an α-Helix to β-Strand Conformation Switch in MEF2B

Lei, Xiao; Kou, Yi; Fu, Yang; Rajashekar, Niroop; Shi, Haoran; Wu, Fang; Xu, Jiang; Luo, Yibing; Chen, Lin

doi:10.1016/j.jmb.2018.02.012

Cited by 33 publications

(20 citation statements)

References 85 publications

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“…The majority of MEF2B mutations found in DLBCL and follicular lymphomas (FL) affect three hot spots which are absent from MCL, namely K4, D69, and D8343,45 . These mutations have been described to alter DNA or co-repressor binding by MEF2B, resulting in constitutive expression of MEF2B target genes[46][47][48] . The distinct hot spot at K23 and paucity of DLBCL/FL-related mutations implies a different role of MEF2B mutations in MCL.…”

mentioning

confidence: 99%

Coding and non-coding drivers of mantle cell lymphoma identified through exome and genome sequencing

Pararajalingam¹,

Coyle²,

Arthur³

et al. 2019

Preprint

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Key points• RNA-binding proteins with roles in regulating alternative splicing, DAZAP1, EWSR1, HNRNPH1, are frequently mutated in MCL • The majority of recurrent somatic HNRNPH1 mutations are intronic and HNRNPH1 exhibits self-regulation through alternative splicing AbstractMantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established and the features known to contribute to differences in clinical course remain limited.To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes alongside previously published exome cohorts. To confirm our findings, we re-sequenced the genes identified in the exome cohort in 212 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations and further nominate two additional genes, EWSR1 and MEF2B, whose mutation respectively associated with poor and good outcome. Our sequencing revealed novel recurrent mutations including a unique missense hot spot in MEF2B and a pattern of non-coding mutations surrounding a single exon of the HNRNPH1 gene. We sequenced the whole genomes of 34 MCLs to confirm the focal nature of HNRNPH1 mutations. Using RNA-seq data from 110 of these cases, we identified a functional role for recurrent non-coding HNRNPH1 mutations in disrupting an auto-regulatory feedback mechanism. Overall, we identified three novel MCL-related genes with roles in RNA trafficking or splicing, namely DAZAP1, EWSR1, and HNRNPH1. Taken together, these data strongly implicate a role for aberrant regulation of splicing in MCL pathobiology.

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confidence: 99%

Coding and non-coding drivers of mantle cell lymphoma identified through exome and genome sequencing

Pararajalingam¹,

Coyle²,

Arthur³

et al. 2019

Preprint

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“…As more fold switchers are discovered, we anticipate that their biological scope will expand. For example, a single cancer-associated mutation changes a native a-helix in MEF2B to a b-strand (Lei et al, 2018), indicating that single-nucleotide polymorphisms could induce fold switching and lead to disease. Furthermore, post-translational modifications can lead to dramatic functionally relevant structural changes in IDPs (Bah et al, 2015), suggesting that the same might be true for fold switchers.…”

Section: Discussionmentioning

confidence: 99%

Functional and Regulatory Roles of Fold-Switching Proteins

Kim

Porter

2021

Structure

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“…Accurately predicting evolved fold switchers from their genomic sequences would be useful because there are biologically relevant examples in which one or several mutations in a protein can lead to structural changes associated with disease (16) or different cellular behaviors (17). We also hypothesized that this approach could be more successful on evolved fold-switchers than on extant fold switchers because evolved fold switchers tend to have only one visible folded state by NMR (9,14,23,24), and they may only adopt a single fold, as in the cases of the Cro/cI proteins and some GA/GB variants.…”

Section: Discussionmentioning

confidence: 99%

“…The third set of evolved fold switchers, GA98 and GA98, arose from a combination of directed evolution and rational protein design (11,15). Remarkably, these protein variants are 98% identical ( sequence variations exist between even closely-related eukaryotes, and some evidence suggests that these variations can lead to structural remodeling associated with disease (16) or contribute to cellular behaviors (17). Unfortunately, the current examples of naturally evolved fold switchers were stumbled upon by chance rather than detected by predictive methods.…”

Section: Introductionmentioning

confidence: 99%

A method for predicting evolved fold switchers exclusively from their sequences

Kim

Looger

Porter

2020

Preprint

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Although most proteins with known structures conform to the longstanding rule-of-thumb that high levels of aligned sequence identity tend to indicate similar folds and functions, an increasing number of exceptions is emerging. In spite of having highly similar sequences, these "evolved fold switchers" (1) can adopt radically different folds with disparate biological functions. Predictive methods for identifying evolved fold switchers are desirable because some of them are associated with disease and/or can perform different functions in cells. Previously, we showed that inconsistencies between predicted and experimentally determined secondary structures can be used to predict fold switching proteins (2). The usefulness of this approach is limited, however, because it requires experimentally determined protein structures, whose magnitude is dwarfed by the number of genomic proteins. Here, we use secondary structure predictions to identify evolved fold switchers from their amino acid sequences alone. To do this, we looked for inconsistencies between the secondary structure predictions of the alternative conformations of evolved fold switchers. We used three different predictors in this study: JPred4, PSIPRED, and SPIDER3. We find that overall inconsistencies are not a significant predictor of evolved fold switchers for any of the three predictors.Inconsistencies between a-helix and b-strand predictions made by JPred4, however, can discriminate between the different conformations of evolved fold switchers with statistical significance (p < 1.7*10 -13 ). In light of this observation, we used these inconsistencies as a classifier and found that it could robustly discriminate between evolved fold switchers and evolved non-fold-switchers, as evidenced by a Matthews correlation coefficient of 0.90. These results indicate that inconsistencies between secondary structure predictions can indeed be used to identify evolved fold switchers from their genomic sequences alone. Our findings have implications for genomics, structural biology, and human health.

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The Cancer Mutation D83V Induces an α-Helix to β-Strand Conformation Switch in MEF2B

Cited by 33 publications

References 85 publications

Coding and non-coding drivers of mantle cell lymphoma identified through exome and genome sequencing

Coding and non-coding drivers of mantle cell lymphoma identified through exome and genome sequencing

Functional and Regulatory Roles of Fold-Switching Proteins

A method for predicting evolved fold switchers exclusively from their sequences

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