Structural and functional deviations in disease-associated p97 mutants.

Journal of Structural Biology
Wai Kwan Tang, Di Xia

Abstract

Missense mutations that occur at the interface between two functional domains in the AAA protein p97 lead to suboptimal performance in its enzymatic activity and impaired intracellular functions, causing human disorders such as inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia (IBMPFD). Much progress has been made in characterizing these mutants at cellular, sub-cellular and molecular levels, gaining a substantial understanding of the involvement of p97 in various cellular pathways. At the tissue level, patient biopsies revealed co-localization of p97 with pathologic proteineous inclusions and rimmed vacuoles, which can be reproduced in various cellular and animal models of IBMPFD. At the subcellular level, alterations in p97's ability to bind various adaptor proteins have been demonstrated for some but not all binding partners. Biochemical and biophysical characterizations of pathogenic p97 revealed altered nucleotide binding properties in the D1-domains compared to the wild type. Structural studies showed that mutant p97 are capable of undergoing a uniform transition in the N-domain from a Down- to an Up-conformation in the presence of ATPγS, while in the wild-type p97, this confo...Continue Reading

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Citations

Oct 23, 2013·PLoS Computational Biology·Andreas Spitzmüller, Jordi Mestres
Sep 1, 2015·FEBS Letters·Alexander BuchbergerPetra Hänzelmann
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Apr 27, 2016·Chembiochem : a European Journal of Chemical Biology·Taehyung C LeeAshok A Deniz
Jul 1, 2017·Frontiers in Molecular Biosciences·Yihong YeDi Xia

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