Conformational dynamics and DNA recognition by human MutSbeta

Lee, J.-H.; Thomsen, M.; Daub, H.; Steinbacher, S. C.; Sztyler, A.; Thieulin-Pardo, G.; Neudegger, T.; Plotnikov, N. V.; Iyer, R. R.; Wilkinson, H. A.; Monteagudo, E.; Felsenfeld, D. P.; Haque, T. S.; Finley, M.; Dominguez, C.; Vogt, T. F.; Prasad, B. C.

doi:10.1101/2023.05.08.539930

bioRxiv · 10.1101/2023.05.08.539930

Conformational dynamics and DNA recognition by human MutSbeta

Lee, J.-H.·Thomsen, M.·Daub, H.·Steinbacher, S. C.·Sztyler, A.·Thieulin-Pardo, G.·Neudegger, T.·Plotnikov, N. V.·Iyer, R. R.·Wilkinson, H. A.·Monteagudo, E.·Felsenfeld, D. P.·Haque, T. S.·Finley, M.·Dominguez, C.·Vogt, T. F.·Prasad, B. C.

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Abstract

Human and mouse genetic studies have demonstrated a role for DNA mismatch repair (MMR) molecular machines in modulating the rate of somatic expansion of the huntingtin (HTT) CAG repeats, and onset and progression of Huntingtons Disease (HD). MutS{beta}, a key component of the MMR pathway, is a heterodimeric protein of MSH2 and MSH3 that recognizes and initiates the repair of extrahelical DNA extrusions. Loss-of-function of mouse Msh3 and reduced-expression alleles of human MSH3 lead to slower rates of somatic expansion and delayed disease onset in humans, signifying MSH3 as a promising therapeutic target for HD. Here we report biochemical and cryo-electron microscopy analyses of human MutS{beta}, demonstrating MutS{beta} undergoes conformational changes induced by nucleotide and DNA binding. We present multiple conformations of MutS{beta} including the DNA-free MutS{beta} compatible with homoduplex DNA binding, two distinct structures of MutS{beta} bound to (CAG)2 DNA, a sliding clamp form and a DNA-unbound, ATP-bound conformation. Along with evidence for novel conformational states adopted by MutS{beta} to initiate the MMR cascade, these structures provide a foundation for structure-guided drug discovery.

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Lee, J.-H., Thomsen, M., Daub, H., Steinbacher, S. C., Sztyler, A., Thieulin-Pardo, G., Neudegger, T., Plotnikov, N. V., Iyer, R. R., Wilkinson, H. A., Monteagudo, E., Felsenfeld, D. P., Haque, T. S., Finley, M., Dominguez, C., Vogt, T. F., Prasad, B. C.. 2023-05-10. Conformational dynamics and DNA recognition by human MutSbeta. https://doi.org/10.1101/2023.05.08.539930

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