NDLI: Protein interaction profiling of the p97 adaptor UBXD1 points to a role for the complex in modulating ERGIC-53 trafficking.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Haines, Dale S. Lee, J. Eugene Beauparlant, Stephen L. Kyle, Dane B. Den Besten, Willem Sweredoski, Michael J. Graham, Robert L. J. Hess, Sonja Deshaies, Raymond J.
Description	Country affiliation: United States Author Affiliation: Haines DS ( Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, 19104 Pennsylvania, USA.)
Abstract	UBXD1 is a member of the poorly understood subfamily of p97 adaptors that do not harbor a ubiquitin association domain or bind ubiquitin-modified proteins. Of clinical importance, p97 mutants found in familial neurodegenerative conditions Inclusion Body Myopathy Paget's disease of the bone and/or Frontotemporal Dementia and Amyotrophic Lateral Sclerosis are defective at interacting with UBXD1, indicating that functions regulated by a p97-UBXD1 complex are altered in these diseases. We have performed liquid chromatography-mass spectrometric analysis of UBXD1-interacting proteins to identify pathways in which UBXD1 functions. UBXD1 displays prominent association with ERGIC-53, a hexameric type I integral membrane protein that functions in protein trafficking. The UBXD1-ERGIC-53 interaction requires the N-terminal 10 residues of UBXD1 and the C-terminal cytoplasmic 12 amino acid tail of ERGIC-53. Use of p97 and E1 enzyme inhibitors indicate that complex formation between UBXD1 and ERGIC-53 requires the ATPase activity of p97, but not ubiquitin modification. We also performed SILAC-based quantitative proteomic profiling to identify ERGIC-53 interacting proteins. This analysis identified known (e.g. COPI subunits) and novel (Rab3GAP1/2 complex involved in the fusion of vesicles at the cell membrane) interactions that are also mediated through the C terminus of the protein. Immunoprecipitation and Western blotting analysis confirmed the proteomic interaction data and it also revealed that an UBXD1-Rab3GAP association requires the ERGIC-53 binding domain of UBXD1. Localization studies indicate that UBXD1 modules the sub-cellular trafficking of ERGIC-53, including promoting movement to the cell membrane. We propose that p97-UBXD1 modulates the trafficking of ERGIC-53-containing vesicles by controlling the interaction of transport factors with the cytoplasmic tail of ERGIC-53.
File Format	HTM / HTML
ISSN	15359476
e-ISSN	15359484
DOI	10.1074/mcp.M111.016444
Journal	Molecular & Cellular Proteomics
Issue Number	6
Volume Number	11
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2012-06-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Proteomics Carrier Proteins Metabolism Mannose-binding Lectins Membrane Proteins Adenosine Triphosphatases Antagonists & Inhibitors Benzoates Pharmacology Chemistry Cell Line, Tumor Furans Nuclear Proteins Protein Binding Protein Interaction Domains And Motifs Protein Interaction Mapping Protein Transport Pyrazoles Quinazolines Secretory Vesicles Ubiquitin-activating Enzymes Rab3 Gtp-binding Proteins Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Medicine Analytical Chemistry Molecular Biology Biochemistry

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Protein Interaction Profiling of the p97 Adaptor UBXD1 Points to a Role for the Complex in Modulating ERGIC-53 Trafficking*

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