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Specificity in protein-ligand recognition: characterisation of a novel conformational switch in the p62 UBA domain interaction with ubiquitin

蛋白质-配体识别的特异性：p62 UBA 结构域与泛素相互作用中新型构象开关的表征

基本信息

批准号：
BB/F013663/1
负责人：
Mark Searle
金额：
$ 42.99万
依托单位：
University of Nottingham
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2008
资助国家：
英国
起止时间：
2008 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FF013663%2F1
关键词：
Specificity protein ligand recognition characterisation

项目摘要

The multi-functional p62 protein (also known as SQSTM1) regulates a diverse range of cellular processes involving in vivo interaction partners relevant to bone cell (osteoclast) and neuronal function. Mutations affecting p62 are a common cause of Paget's disease of bone (PDB), however, the precise disease mechanism in this skeletal disorder is unclear. Ubiquitin-associated (UBA) domains have been identified in many proteins as ubiquitin (Ub)-binding motifs; PDB mutations in p62 occur principally within its C-terminal UBA domain, with the implication that these pathological mutations may compromise interactions of the p62 protein with osteoclast protein targets already tagged with ubiquitin. More recently, mutations in other parts of the p62 sequence have been identified in PDB patients which still result in loss or impairment of ubiquitin-binding function. In structural studies of the UBA domain of p62 and its interaction with ubiquitin and poly-ubiquitin chains, we have recently demonstrated a novel structural re-organisation of the UBA upon binding ubiquitin that appears to provide an unique mechanism for specific regulation of ubiquitin-binding, given the participation of p62 in multiple signalling complexes. This binding mechanism suggests that PDB mutations in the UBA domain could affect ubiquitin binding specificity through both direct and indirect mechanisms that affect this conformational equilibrium. We plan to investigate the molecular origins of the interaction of much larger fragments of the p62 protein than simply the UBA domain, and investigate the underlying physiological basis for ubiquitin recognition with PDB mutations as valuable tools.

多功能p62蛋白（也称为SQSTM 1）调节多种细胞过程，涉及与骨细胞（破骨细胞）和神经元功能相关的体内相互作用伴侣。影响p62的突变是佩吉特骨病（PDB）的常见原因，然而，这种骨骼疾病的确切发病机制尚不清楚。泛素相关（乌巴）结构域在许多蛋白质中被鉴定为泛素（Ub）结合基序; p62中的PDB突变主要发生在其C-末端乌巴结构域内，暗示这些病理性突变可能损害p62蛋白与已经用泛素标记的破骨细胞蛋白靶的相互作用。最近，在PDB患者中已经鉴定出p62序列的其他部分的突变，其仍然导致泛素结合功能的丧失或损害。在p62的乌巴结构域及其与泛素和多聚泛素链的相互作用的结构研究中，我们最近证明了结合泛素后乌巴的一种新的结构重组，该重组似乎提供了一种独特的机制，用于特异性调节泛素结合，考虑到p62参与多种信号复合物。这种结合机制表明，在乌巴结构域中的PDB突变可以通过影响这种构象平衡的直接和间接机制来影响泛素结合特异性。我们计划研究p62蛋白质的大得多的片段比简单的乌巴域的相互作用的分子起源，并调查潜在的生理基础的泛素识别与PDB突变作为有价值的工具。