- EMDB-15417: human MutSalpha (MSH2/MSH6) binding to DNA with a GT mismatch -
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基本情報
登録情報
データベース: EMDB / ID: EMD-15417
タイトル
human MutSalpha (MSH2/MSH6) binding to DNA with a GT mismatch
マップデータ
試料
複合体: MutSalpha on mismatched DNA
複合体: MSH2
タンパク質・ペプチド: DNA mismatch repair protein Msh2
複合体: MSH6
タンパク質・ペプチド: DNA mismatch repair protein Msh6
複合体: DNA containing a G/T mismatch
DNA: DNA (50-MER)
DNA: DNA (50-MER)
リガンド: MAGNESIUM ION
リガンド: ADENOSINE-5'-DIPHOSPHATE
キーワード
DNA mismatch repair / MMR / MutSa / Lynch Syndrome / DNA BINDING PROTEIN
機能・相同性
機能・相同性情報
somatic recombination of immunoglobulin genes involved in immune response / MutSbeta complex / Defective Mismatch Repair Associated With MSH3 / MutSalpha complex / Defective Mismatch Repair Associated With MSH2 / Defective Mismatch Repair Associated With MSH6 / guanine/thymine mispair binding / somatic recombination of immunoglobulin gene segments / maintenance of DNA repeat elements / B cell mediated immunity ...somatic recombination of immunoglobulin genes involved in immune response / MutSbeta complex / Defective Mismatch Repair Associated With MSH3 / MutSalpha complex / Defective Mismatch Repair Associated With MSH2 / Defective Mismatch Repair Associated With MSH6 / guanine/thymine mispair binding / somatic recombination of immunoglobulin gene segments / maintenance of DNA repeat elements / B cell mediated immunity / positive regulation of helicase activity / positive regulation of isotype switching to IgA isotypes / meiotic mismatch repair / centromeric DNA binding / positive regulation of isotype switching to IgG isotypes / mismatched DNA binding / negative regulation of DNA recombination / isotype switching / mitotic recombination / Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta) / Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) / oxidative phosphorylation / postreplication repair / response to UV-B / mitotic intra-S DNA damage checkpoint signaling / ATP-dependent DNA damage sensor activity / germ cell development / response to X-ray / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / somatic hypermutation of immunoglobulin genes / ATP-dependent activity, acting on DNA / mismatch repair / response to UV / protein localization to chromatin / methylated histone binding / intrinsic apoptotic signaling pathway / B cell differentiation / determination of adult lifespan / TP53 Regulates Transcription of DNA Repair Genes / male gonad development / intrinsic apoptotic signaling pathway in response to DNA damage / double-strand break repair / spermatogenesis / in utero embryonic development / negative regulation of neuron apoptotic process / chromosome, telomeric region / damaged DNA binding / intracellular membrane-bounded organelle / DNA repair / chromatin binding / chromatin / Golgi apparatus / enzyme binding / protein homodimerization activity / ATP hydrolysis activity / DNA binding / nucleoplasm / ATP binding / membrane / nucleus / cytosol 類似検索 - 分子機能
DNA mismatch repair Msh2-type / DNA mismatch repair protein Msh2 / DNA mismatch repair protein MutS/MSH / DNA mismatch repair protein MutS-like, N-terminal / DNA mismatch repair protein MutS, connector domain / DNA mismatch repair protein MutS, clamp / DNA mismatch repair protein MutS, N-terminal / MutS, connector domain superfamily / MutS domain I / MutS domain II ...DNA mismatch repair Msh2-type / DNA mismatch repair protein Msh2 / DNA mismatch repair protein MutS/MSH / DNA mismatch repair protein MutS-like, N-terminal / DNA mismatch repair protein MutS, connector domain / DNA mismatch repair protein MutS, clamp / DNA mismatch repair protein MutS, N-terminal / MutS, connector domain superfamily / MutS domain I / MutS domain II / MutS family domain IV / MutS domain III / DNA mismatch repair MutS family / DNA mismatch repair protein MutS, C-terminal / DNA mismatch repair protein MutS, core / DNA mismatch repair protein MutS, core domain superfamily / MutS domain V / DNA mismatch repair proteins mutS family signature. / DNA-binding domain of DNA mismatch repair MUTS family / ATPase domain of DNA mismatch repair MUTS family / domain with conserved PWWP motif / PWWP domain / PWWP domain profile. / PWWP domain / P-loop containing nucleoside triphosphate hydrolase 類似検索 - ドメイン・相同性
DNA mismatch repair protein Msh2 / DNA mismatch repair protein Msh6 類似検索 - 構成要素
Netherlands Organisation for Scientific Research (NWO)
NOW-TOP 714.016.002
オランダ
European Commission
H2020-MSCA-ITN-2016 722433 DNAREPAIRMAN
European Union
引用
ジャーナル: Nucleic Acids Res / 年: 2023 タイトル: Unexpected moves: a conformational change in MutSα enables high-affinity DNA mismatch binding. 著者: Susanne R Bruekner / Wietske Pieters / Alexander Fish / A Manuel Liaci / Serge Scheffers / Emily Rayner / Daphne Kaldenbach / Lisa Drost / Marleen Dekker / Sandrine van Hees-Stuivenberg / ...著者: Susanne R Bruekner / Wietske Pieters / Alexander Fish / A Manuel Liaci / Serge Scheffers / Emily Rayner / Daphne Kaldenbach / Lisa Drost / Marleen Dekker / Sandrine van Hees-Stuivenberg / Elly Delzenne-Goette / Charlotte de Konink / Hellen Houlleberghs / Hendrikus Jan Dubbink / Abeer AlSaegh / Niels de Wind / Friedrich Förster / Hein Te Riele / Titia K Sixma / 要旨: The DNA mismatch repair protein MutSα recognizes wrongly incorporated DNA bases and initiates their correction during DNA replication. Dysfunctions in mismatch repair lead to a predisposition to ...The DNA mismatch repair protein MutSα recognizes wrongly incorporated DNA bases and initiates their correction during DNA replication. Dysfunctions in mismatch repair lead to a predisposition to cancer. Here, we study the homozygous mutation V63E in MSH2 that was found in the germline of a patient with suspected constitutional mismatch repair deficiency syndrome who developed colorectal cancer before the age of 30. Characterization of the mutant in mouse models, as well as slippage and repair assays, shows a mildly pathogenic phenotype. Using cryogenic electron microscopy and surface plasmon resonance, we explored the mechanistic effect of this mutation on MutSα function. We discovered that V63E disrupts a previously unappreciated interface between the mismatch binding domains (MBDs) of MSH2 and MSH6 and leads to reduced DNA binding. Our research identifies this interface as a 'safety lock' that ensures high-affinity DNA binding to increase replication fidelity. Our mechanistic model explains the hypomorphic phenotype of the V63E patient mutation and other variants in the MBD interface.