| Autor: |
Jung-Hoon Lee, Maren Thomsen, Herwin Daub, Stefan C. Steinbacher, Agnieszka Sztyler, Gabriel Thieulin-Pardo, Tobias Neudegger, Nikolay V. Plotnikov, Ravi R. Iyer, Hilary A. Wilkinson, Edith Monteagudo, Dan P. Felsenfeld, Tasir S. Haque, Michael Finley, Celia Dominguez, Thomas F. Vogt, Brinda C. Prasad |
| Rok vydání: |
2023 |
| Popis: |
Huntington’s disease (HD) is fatal neurodegenerative disorder caused by the expansion of a CAG-repeat tract in the huntingtin (HTT) gene. Human and mouse genetics studies have demonstrated a role for DNA mismatch repair (MMR) proteins which control the rate of somatic expansion of theHTTCAG repeat and disease onset and progression. MutSβ, a key member of the MMR pathway, is a heterodimeric protein of MSH2 and MSH3 that recognizes and initiates the repair of small insertion or deletion DNA loop outs. Both mouseMsh3loss-of-function and reduced-expression alleles of humanMSH3lead to slower rates of somatic expansion in theHTTCAG tract and a delay of disease onset and progression, signifying MSH3 as a promising drug target for HD. Structural biology studies of MutSβ are informative for mechanism, protein structure-function relationships, and guiding small-molecule drug design. Here we report biochemical and cryo-electron microscopy analyses of human MutSβ ensembles, revealing that MutSβ undergoes multiple conformational changes in response to binding and release of nucleotides and DNA. The DNA-free MutSβ-ADP complex adopts an open conformation that is compatible with DNA binding. The conformation of MutSβ in the (CAG)2DNA-bound open structure most closely resembles the recently identified low-affinity state of MutSα, compared to the canonical mismatch-bound conformation. The homoduplex-bound and DNA-unbound MutSβ-ATP structures show that MutSβ undergoes an ATP-dependent conformational change towards sliding clamp forms. This study provides a comprehensive understanding of the structural conformational dynamics of MutSβ, insights into the MMR cascade, and a foundation for structure-guided drug discovery. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
