Structure and Function of the PLAA/Ufd3-p97/Cdc48 Complex

Liyan Qiu; Natasha Pashkova; John R. Walker; Stanley Winistorfer; Abdellah Allali-Hassani; Masato Akutsu; Robert Piper; Sirano Dhe-Paganon

doi:10.1074/jbc.M109.044685

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Structure and Function of the PLAA/Ufd3-p97/Cdc48 Complex

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Structure and Function of the PLAA/Ufd3-p97/Cdc48 Complex

Liyan Qiu, Natasha Pashkova, John R. Walker, Stanley Winistorfer, Abdellah Allali-Hassani, Masato Akutsu, Robert Piper and Sirano Dhe-Paganon

The Journal of biological chemistry, Vol.285(1), pp.365-372

01/01/2010

DOI: 10.1074/jbc.M109.044685

PMCID: PMC2804184

PMID: 19887378

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Abstract

PLAA (ortholog of yeast Doa1/Ufd3, also know as human PLAP or phospholipase A2-activating protein) has been implicated in a variety of disparate biological processes that involve the ubiquitin system. It is linked to the maintenance of ubiquitin levels, but the mechanism by which it accomplishes this is unclear. The C-terminal PUL (PLAP, Ufd3p, and Lub1p) domain of PLAA binds p97, an AAA ATPase, which among other functions helps transfer ubiquitinated proteins to the proteasome for degradation. In yeast, loss of Doa1 is suppressed by altering p97/Cdc48 function indicating that physical interaction between PLAA and p97 is functionally important. Although the overall regions of interaction between these proteins are known, the structural basis has been unavailable. We solved the high resolution crystal structure of the p97-PLAA complex showing that the PUL domain forms a 6-mer Armadillo-containing domain. Its N-terminal extension folds back onto the inner curvature forming a deep ridge that is positively charged with residues that are phylogenetically conserved. The C terminus of p97 binds in this ridge, where the side chain of p97-Tyr(805), implicated in phosphorylation-dependent regulation, is buried. Expressed in doa1 Delta null cells, point mutants of the yeast ortholog Doa1 that disrupt this interaction display slightly reduced ubiquitin levels, but unlike doa1 Delta null cells, showed only some of the growth phenotypes. These data suggest that the p97-PLAA interaction is important for a subset of PLAA-dependent biological processes and provides a framework to better understand the role of these complex molecules in the ubiquitin system.

Biochemistry & Molecular Biology

Life Sciences & Biomedicine

Science & Technology

Details

Title: Subtitle: Structure and Function of the PLAA/Ufd3-p97/Cdc48 Complex
Creators: Liyan Qiu - University of Toronto
Natasha Pashkova - University of Iowa
John R. Walker - Structural Genomics Consortium
Stanley Winistorfer - University of Iowa
Abdellah Allali-Hassani - Structural Genomics Consortium
Masato Akutsu - University of Toronto
Robert Piper - University of Iowa
Sirano Dhe-Paganon - University of Toronto
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.285(1), pp.365-372
DOI: 10.1074/jbc.M109.044685
PMID: 19887378
PMCID: PMC2804184
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: Amer Soc Biochemistry Molecular Biology Inc
Number of pages: 8
Grant note: R01GM058202 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) RO1 GM58202 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
Language: English
Date published: 01/01/2010
Academic Unit: Molecular Physiology and Biophysics; Medicine Administration; Internal Medicine
Record Identifier: 9984297491902771

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