4KOD

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

Summary for 4KOD

• Entry DOI: 10.2210/pdb4kod/pdb
• Related: 4KLN 4KO8
• Descriptor: Transitional endoplasmic reticulum ATPase, ADENOSINE-5'-DIPHOSPHATE (3 entities in total)
• Functional Keywords: aaa atpase, transport protein, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytosol: P55072
• Total number of polymer chains: 12
• Total formula weight: 659873.60

Authors

Xia, D.,Tang, W.K. (deposition date: 2013-05-11, release date: 2013-11-13, Last modification date: 2024-02-28)

Primary citation

Tang, W.K.,Xia, D.
Altered Intersubunit Communication Is the Molecular Basis for Functional Defects of Pathogenic p97 Mutants.
J.Biol.Chem., 288:36624-36635, 2013

PubMed Abstract: The human AAA ATPase p97 is a molecular chaperone essential in cellular proteostasis. Single amino acid substitutions in p97 have been linked to a clinical multiple-disorder condition known as inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia. How the mutations affect the molecular mechanism that governs the function of p97 remains unclear. Here, we show that within the hexameric ring of a mutant p97, D1 domains fail to regulate their respective nucleotide-binding states, as evidenced by the lower amount of prebound ADP, weaker ADP binding affinity, full occupancy of adenosine-5'-O-(3-thiotriphosphate) binding, and elevated overall ATPase activity, indicating a loss of communication among subunits. Defective communication between subunits is further illustrated by altered conformation in the side chain of residue Phe-360 that probes into the nucleotide-binding pocket from a neighboring subunit. Consequently, conformations of N domains in a hexameric ring of a mutant p97 become uncoordinated, thus impacting its ability to process substrate.

PubMed: 24196964
DOI: 10.1074/jbc.M113.488924

Experimental method

X-RAY DIFFRACTION (2.96 Å)