A novel ATP-dependent conformation in p97 N-D1 fragment revealed by crystal structures of disease-related mutants

Journal Article · Thu Nov 11 04:00:00 EST 2010 · EMBO J.

DOI:https://doi.org/10.1038/emboj.2010.104· OSTI ID:1002527

Tang, Wai Kwan; Li, Dongyang; Li, Chou-chi; Esser, Lothar; Dai, Renming; Guo, Liang; Xia1, Di ^[1]

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1. IIT

Mutations in p97, a major cytosolic AAA (ATPases associated with a variety of cellular activities) chaperone, cause inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia (IBMPFD). IBMPFD mutants have single amino-acid substitutions at the interface between the N-terminal domain (N-domain) and the adjacent AAA domain (D1), resulting in a reduced affinity for ADP. The structures of p97 N-D1 fragments bearing IBMPFD mutations adopt an atypical N-domain conformation in the presence of Mg{sup 2+} {center_dot} ATP{gamma}S, which is reversible by ADP, showing for the first time the nucleotide-dependent conformational change of the N-domain. The transition from the ADP- to the ATP{gamma}S-bound state is accompanied by a loop-to-helix conversion in the N-D1 linker and by an apparent re-ordering in the N-terminal region of p97. X-ray scattering experiments suggest that wild-type p97 subunits undergo a similar nucleotide-dependent N-domain conformational change. We propose that IBMPFD mutations alter the timing of the transition between nucleotide states by destabilizing the ADP-bound form and consequently interfere with the interactions between the N-domains and their substrates.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1002527
• Journal Information: EMBO J., Journal Name: EMBO J. Journal Issue: (13) ; 2010 Vol. 29; ISSN EMJODG; ISSN 0261-4189
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
AFFINITY
BEARINGS
CONFORMATIONAL CHANGES
CRYSTAL STRUCTURE
DISEASES
MUTANTS
MUTATIONS
NUCLEOTIDES
SCATTERING
SUBSTRATES