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Cooperative subunit dynamics modulate p97 function.

Rui Huang1,2,3,4, Zev A Ripstein5,2, John L Rubinstein5,2,6

  • 1Program in Molecular Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; ruihuangchem@gmail.com kay@pound.med.utoronto.ca.

Proceedings of the National Academy of Sciences of the United States of America
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PubMed
Summary
This summary is machine-generated.

Mutations in p97 ATPase cause neurological disease by altering protein structure. This study reveals how wild-type subunits can correct mutant conformations in heterohexamers, impacting disease.

Keywords:
IBMPFD/MSP1 disease mutationsdomain cooperativitymethyl-TROSYp97/VCPprotein dynamics

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • p97 ATPase is crucial for cellular functions and its mutations cause neurological disorders.
  • Patients with these disorders are heterozygous for wild-type (WT) and mutant p97 alleles, leading to heterogeneous protein complexes.
  • Previous studies focused on homohexamers, limiting understanding of WT/mutant interactions.

Purpose of the Study:

  • To investigate the functional dynamics of N-terminal domains (NTDs) in biologically relevant p97 heterohexamers.
  • To understand how wild-type and mutant subunits interact within the same complex.
  • To elucidate the mechanisms of allosteric communication and adaptor binding in disease-relevant p97 assemblies.

Main Methods:

  • Utilized methyl-transverse relaxation optimized spectroscopy (TROSY) NMR on specifically labeled p97 heterohexamer constructs.
  • Analyzed the equilibrium of NTD conformations (up/down) in response to ADP binding.
  • Investigated the binding of the UBXD1 adaptor to p97 heterohexamers.

Main Results:

  • Demonstrated positive cooperativity in NTD up/down equilibria between neighboring protomers in heterohexamers.
  • Identified interprotomer pathways mediating allosteric communication.
  • Showed that WT p97 subunits can partially restore the NTD conformation and UBXD1 binding in mutant subunits.

Conclusions:

  • p97 exhibits significant plasticity, with subunit interactions influencing overall conformation and function.
  • Allosteric communication between subunits is critical for maintaining normal p97 function.
  • WT subunits can compensate for mutant effects, offering insights into disease mechanisms and potential therapeutic strategies.