Complex of Fas-associated Factor 1 (FAF1) with Valosin-containing Protein (VCP)-Npl4-Ufd1 and Polyubiquitinated Proteins Promotes Endoplasmic Reticulum-associated Degradation (ERAD)
Complex of Fas-associated Factor 1 (FAF1) with Valosin-containing Protein (VCP)-Npl4-Ufd1 and Polyubiquitinated Proteins Promotes Endoplasmic Reticulum-associated Degradation (ERAD)
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DOI：
10.1074/jbc.m112.417576
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发表时间：
2013-03-08
影响因子：
4.8
通讯作者：
Lee, Kong-Joo
中科院分区：
文献类型：
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作者：
Lee, Jae-Jin;Park, Joon Kyu;Lee, Kong-Joo
Fas相关因子1（Fas-associated factor 1，FAF 1）是一种泛素受体，含有多个泛素相关结构域，包括泛素相关（乌巴）、泛素样（UBL）1、UBL 2和泛素调节X（UBX）。我们先前的研究表明，N-末端乌巴结构域识别赖氨酸（48）-泛素连接，以募集多泛素化蛋白，C-末端UBX结构域与含valosin-containing蛋白（VCP）相互作用。该研究表明FAF 1仅与与Np 14-Ufd 1异二聚体复合的VCP相互作用，这是将多泛素化蛋白募集到乌巴结构域的需要。有趣的是，VCP与C-末端UBX结构域的结合调节泛素与N-末端乌巴结构域的结合，而乌巴和UBX结构域之间没有直接的相互作用。这些相互作用通过结构和生物化学分析得到很好的表征。已知VCP-Npl 4-Ufd 1复合物是内质网相关降解所需的机制。我们在这里证明了FAF 1通过UBX结构域与VCP-Npl 4-Ufd 1复合物结合，并通过乌巴结构域与多聚遍在蛋白结合，以促进内质网相关的降解。
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.