3HU3

Structure of p97 N-D1 R155H mutant in complex with ATPgS

Summary for 3HU3

• Entry DOI: 10.2210/pdb3hu3/pdb
• Related: 3HU1 3HU2
• Descriptor: Transitional endoplasmic reticulum ATPase, PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: p97, vcp, transport protein
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytosol: P55072
• Total number of polymer chains: 2
• Total formula weight: 110219.64

Authors

Tang, W.-K. (deposition date: 2009-06-12, release date: 2010-06-16, Last modification date: 2024-02-21)

Primary citation

Tang, W.K.,Li, D.,Li, C.C.,Esser, L.,Dai, R.,Guo, L.,Xia, D.
A novel ATP-dependent conformation in p97 N-D1 fragment revealed by crystal structures of disease-related mutants.
Embo J., 29:2217-2229, 2010

PubMed Abstract: 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(2+).ATPgammaS, 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 ATPgammaS-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.

PubMed: 20512113
DOI: 10.1038/emboj.2010.104

Experimental method

X-RAY DIFFRACTION (2.2 Å)