Abstract
Fas-associated factor 1 (FAF1) is a ubiquitin receptor containing multiple ubiquitin-related domains including ubiquitin-associated (UBA), ubiquitin-like (UBL) 1, UBL2, and ubiquitin regulatory X (UBX). We previously showed that N-terminal UBA domain recognizes Lys(48)-ubiquitin linkage to recruit polyubiquitinated proteins and that a C-terminal UBX domain interacts with valosin-containing protein (VCP). This study shows that FAF1 interacts only with VCP complexed with Npl4-Ufd1 heterodimer, a requirement for the recruitment of polyubiquitinated proteins to UBA domain. Intriguingly, VCP association to C-terminal UBX domain regulates ubiquitin binding to N-terminal UBA domain without direct interaction between UBA and UBX domains. These interactions are well characterized by structural and biochemical analysis. VCP-Npl4-Ufd1 complex is known as the machinery required for endoplasmic reticulum-associated degradation. We demonstrate here that FAF1 binds to VCP-Npl4-Ufd1 complex via UBX domain and polyubiquitinated proteins via UBA domain to promote endoplasmic reticulum-associated degradation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Adaptor Proteins, Vesicular Transport
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Adenosine Triphosphatases / chemistry
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Adenosine Triphosphatases / genetics
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Adenosine Triphosphatases / metabolism*
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Apoptosis Regulatory Proteins
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Binding Sites / genetics
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Blotting, Western
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Cell Cycle Proteins / chemistry
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Crystallography, X-Ray
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Endoplasmic Reticulum-Associated Degradation*
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HEK293 Cells
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HeLa Cells
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Humans
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Intracellular Signaling Peptides and Proteins
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Microscopy, Electron
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Models, Molecular
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Multiprotein Complexes / chemistry
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Multiprotein Complexes / metabolism
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Multiprotein Complexes / ultrastructure
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Mutation
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Polyubiquitin / metabolism
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Protein Binding
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Protein Multimerization
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Protein Structure, Tertiary
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Proteins / chemistry
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Proteins / genetics
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Proteins / metabolism*
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Ubiquitin / metabolism
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Valosin Containing Protein
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Apoptosis Regulatory Proteins
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Cell Cycle Proteins
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FAF1 protein, human
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Intracellular Signaling Peptides and Proteins
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Multiprotein Complexes
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NPLOC4 protein, human
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Nuclear Proteins
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Proteins
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UFD1 protein, human
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Ubiquitin
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Polyubiquitin
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Adenosine Triphosphatases
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VCP protein, human
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Valosin Containing Protein