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A novel ATP dependent conformational change of p97 ND1 fragment revealed by crystal structures of disease related mutants
Author(s) -
Tang Wai Kwan,
Li ChouChi,
Xia Di
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.907.6
Subject(s) - mutant , random hexamer , atp hydrolysis , wild type , conformational change , nucleotide , chemistry , cyclic nucleotide binding domain , biophysics , biochemistry , microbiology and biotechnology , biology , enzyme , atpase , gene
Mutations in human p97, a type II AAA+ protein, have been implicated in IBMPFD (Inclusion Body Myopathy associated with Paget's disease of the bone and Frontotemporal Dementia). Previous crystallographic analyses showed that wild type p97 are invariably bound with ADP in the D1‐domain. Here, we show the crystal structures of ND1 fragment of the disease‐related p97 mutants, for the first time, with ATPγS bound in the D1‐domain. In the present structure, the N‐domain undergoes rotational and translational movement. This conformational change has been confirmed to be nucleotide‐driven as the movement is reversible by ADP. We found that the amount of prebound ADP in D1‐domain is consistently lower in mutants. Interestingly, titration with ATPγS revealed two types of binding sites in the mutants but not in wild type p97, suggesting the ADP‐prebound D1 sites can be occupied by ATPγS in the case of mutants but not in wild type. We believe that the non‐uniform nucleotide‐binding states of D1 in various subunits of wild type p97 hexamer are essential for its function. External stimulus such as ATP hydrolysis in D2‐domain or interaction with adaptor proteins may be needed to trigger the nucleotide exchange at the ADP‐prebound sites of wild type p97. The present work also shed light into how the mutations might affect the function of p97 leading to the disease.