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-Structure paper
タイトル | Structural insight and characterization of human Twinkle helicase in mitochondrial disease. |
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ジャーナル・号・ページ | Proc Natl Acad Sci U S A, Vol. 119, Issue 32, Page e2207459119, Year 2022 |
掲載日 | 2022年8月9日 |
著者 | Amanda A Riccio / Jonathan Bouvette / Lalith Perera / Matthew J Longley / Juno M Krahn / Jason G Williams / Robert Dutcher / Mario J Borgnia / William C Copeland / |
PubMed 要旨 | Twinkle is the mammalian helicase vital for replication and integrity of mitochondrial DNA. Over 90 Twinkle helicase disease variants have been linked to progressive external ophthalmoplegia and ...Twinkle is the mammalian helicase vital for replication and integrity of mitochondrial DNA. Over 90 Twinkle helicase disease variants have been linked to progressive external ophthalmoplegia and ataxia neuropathies among other mitochondrial diseases. Despite the biological and clinical importance, Twinkle represents the only remaining component of the human minimal mitochondrial replisome that has yet to be structurally characterized. Here, we present 3-dimensional structures of human Twinkle W315L. Employing cryo-electron microscopy (cryo-EM), we characterize the oligomeric assemblies of human full-length Twinkle W315L, define its multimeric interface, and map clinical variants associated with Twinkle in inherited mitochondrial disease. Cryo-EM, crosslinking-mass spectrometry, and molecular dynamics simulations provide insight into the dynamic movement and molecular consequences of the W315L clinical variant. Collectively, this ensemble of structures outlines a framework for studying Twinkle function in mitochondrial DNA replication and associated disease states. |
リンク | Proc Natl Acad Sci U S A / PubMed:35914129 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.8 - 4.5 Å |
構造データ | EMDB-25743, PDB-7t8b: EMDB-25744, PDB-7t8c: EMDB-25746: Octameric Twinkle Helicase Clinical Variant W315L, local refinement |
由来 |
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キーワード | DNA BINDING PROTEIN / Helicase / walker A / walker B / DNA binding |