Structural basis for nucleotide-modulated p97 association with the ER membrane
Wai Kwan Tang1, Ting Zhang2, Yihong Ye2
1Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Cell Discovery
|December 15, 2017
Summary
The cytosolic protein p97 binds ER membranes via VIMP, regulated by its N domain's nucleotide-dependent switch. This mechanism is impaired in pathogenic mutants, impacting cellular processes.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The AAA protein p97 is crucial for cellular functions like ER-associated degradation.
- p97's N domain undergoes nucleotide-dependent conformational changes, but their physiological significance is unknown.
- p97 associates with membranes, a process vital for its functions.
Purpose of the Study:
- To investigate the physiological relevance of p97's nucleotide-dependent N domain conformational switch.
- To elucidate the mechanism of p97 recruitment to ER membranes.
- To understand how pathogenic mutations affect p97's membrane association.
Main Methods:
- Structural analysis of p97, VIMP, and their complexes.
- Biochemical assays to study nucleotide-dependent conformational changes.
- Analysis of wild-type and mutant p97 interactions with ER membranes.
Main Results:
- p97 is recruited to ER membranes primarily through interaction with VIMP.
- Nucleotide-dependent N domain conformational switch modulates p97 recruitment in wild-type but not mutant forms.
- Structural data reveals the molecular mechanism of modulation and identifies altered N-D1 domain interactions in mutants.
Conclusions:
- The nucleotide-modulated membrane association of p97 is physiologically relevant and mediated by VIMP.
- Pathogenic mutations disrupt this modulation due to altered domain interactions.
- This mechanism may be important for other p97-dependent cellular processes.
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