Structural role of a unique p62 UBA dimer in the regulation of signal transduction and autophagy

独特的p62 UBA二聚体在信号转导和自噬调节中的结构作用

• 批准号: BB/I011420/1
• 负责人: Mark Searle
• 金额: $ 48.27万
• 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: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI011420%2F1
• 关键词: Structural; role; unique; p62; UBA

p62 is a multi-functional scaffold protein (also known as SQSTM1) which regulates a diverse range of cellular processes involving in vivo interaction partners relevant to bone cell (osteoclast), neuronal function and autophagetic clearance of protein aggregates from cells. Mutations in p62 are a common cause of Paget's disease of bone (PDB), however, the precise disease mechanism in this skeletal disorder is unclear. P62 is a ubiquitin-binding receptor and uses a UBA domain to achieve binding and recognition of ubiquitin. PDB mutations in p62 occur principally within the UBA recognition motif of p62, 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. We have recently demonstrated that the UBA domain of p62 is unique amongst this family of ubiquitin binding domains (UBDs) in forming a highly stable 'biologically inactive' dimer which appears to regulate the binding to poly-ubiquitin chains. The stability of the dimer also appears to be directly correlated with levels of NF-kB signalling activity in osteoclasts, linked to bone metabolism. Given the participation of p62 in multiple signalling complexes, the stability of the UBA dimer and the subsequent effects of PDB mutations will be investigated at the molecular and structural level to shed light on the physiological relevance of the formation of the p62 UBA dimer on p62's mode of action and the possible links to dysfunctional regulation of protein-protein interactions and human disease that result from mutations within the p62 receptor.

p62是一种多功能支架蛋白（也称为SQSTM 1），其调节多种细胞过程，包括与骨细胞（破骨细胞）相关的体内相互作用伴侣、神经元功能和蛋白质聚集体从细胞中的自噬清除。p62基因突变是佩吉特骨病（PDB）的常见病因，然而，这种骨骼疾病的确切发病机制尚不清楚。P62是一种泛素结合受体，利用乌巴结构域实现对泛素的结合和识别。p62中的PDB突变主要发生在p62的乌巴识别基序内，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。我们最近证明p62的乌巴结构域在形成高度稳定的“生物学上无活性的”二聚体方面是泛素结合结构域（UBD）家族中唯一的，所述二聚体似乎调节与多聚泛素链的结合。二聚体的稳定性似乎也与破骨细胞中NF-κ B信号传导活性的水平直接相关，这与骨代谢有关。鉴于p62参与多种信号复合物，将在分子和结构水平上研究乌巴二聚体的稳定性和PDB突变的后续影响，以阐明p62乌巴二聚体形成对p62作用模式的生理相关性以及与蛋白质功能失调调节的可能联系。蛋白质相互作用和p62受体内突变引起的人类疾病。

项目成果

ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling.

• DOI: 10.1016/j.mcn.2016.08.004
• 发表时间: 2016-10
• 期刊: Molecular and cellular neurosciences
• 作者: Goode A;Rea S;Sultana M;Shaw B;Searle MS;Layfield R
• 通讯作者: Layfield R

Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD.

• DOI: 10.1080/15548627.2016.1170257
• 发表时间: 2016-07-02
• 期刊: Autophagy
• 影响因子: 13.3
• 作者: Goode A;Butler K;Long J;Cavey J;Scott D;Shaw B;Sollenberger J;Gell C;Johansen T;Oldham NJ;Searle MS;Layfield R
• 通讯作者: Layfield R

Structural insights into the targeting of mRNA GU-rich elements by the three RRMs of CELF1.

• DOI: 10.1093/nar/gkt470
• 发表时间: 2013-08
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Edwards JM;Long J;de Moor CH;Emsley J;Searle MS
• 通讯作者: Searle MS

Paget disease of bone-associated UBA domain mutations of SQSTM1 exert distinct effects on protein structure and function.

• DOI: 10.1016/j.bbadis.2014.03.006
• 发表时间: 2014-07
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
• 影响因子: 6.2
• 作者: Goode, Alice;Long, Jed E.;Shaw, Barry;Ralston, Stuart H.;Visconti, Micaela Rios;Gianfrancesco, Fernando;Esposito, Teresa;Gennari, Luigi;Merlotti, Daniela;Rendina, Domenico;Rea, Sarah L.;Sultana, Melanie;Searle, Mark S.;Layfield, Robert
• 通讯作者: Layfield, Robert