Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases

被引：335

作者：

Riley, B. E. ^{[1
]}

Lougheed, J. C. ^{[1
]}

Callaway, K. ^{[1
]}

Velasquez, M. ^{[1
]}

Brecht, E. ^{[1
]}

Nguyen, L. ^{[1
]}

Shaler, T. ^{[2
]}

Walker, D. ^{[1
]}

Yang, Y. ^{[1
]}

Regnstrom, K. ^{[1
]}

Diep, L. ^{[1
]}

Zhang, Z. ^{[1
]}

Chiou, S. ^{[1
]}

Bova, M. ^{[1
]}

Artis, D. R. ^{[1
]}

Yao, N. ^{[1
]}

Baker, J. ^{[1
]}

Yednock, T. ^{[1
]}

Johnston, J. A. ^{[1
]}

机构：

[1] Elan Pharmaceut, San Francisco, CA 94080 USA

[2] SRI Int, Menlo Pk, CA 94025 USA

来源：

NATURE COMMUNICATIONS | 2013年 / 4卷

基金：

美国国家卫生研究院;

关键词：

DOMAIN; PROTEASOME; IDENTIFICATION; MUTATIONS; MITOCHONDRIA; DEGRADATION; MITOPHAGY; INSIGHTS; FEATURES; DISTINCT;

D O I：

10.1038/ncomms2982

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Parkin is a RING-between-RING E3 ligase that functions in the covalent attachment of ubiquitin to specific substrates, and mutations in Parkin are linked to Parkinson's disease, cancer and mycobacterial infection. The RING-between-RING family of E3 ligases are suggested to function with a canonical RING domain and a catalytic cysteine residue usually restricted to HECT E3 ligases, thus termed 'RING/HECT hybrid' enzymes. Here we present the 1.58 angstrom structure of Parkin-R0RBR, revealing the fold architecture for the four RING domains, and several unpredicted interfaces. Examination of the Parkin active site suggests a catalytic network consisting of C431 and H433. In cells, mutation of C431 eliminates Parkin-catalysed degradation of mitochondria, and capture of an ubiquitin oxyester confirms C431 as Parkin's cellular active site. Our data confirm that Parkin is a RING/HECT hybrid, and provide the first crystal structure of an RING-between-RING E3 ligase at atomic resolution, providing insight into this disease-related protein.

引用

页数：9

共 54 条

[1]

Structure of the Parkin in-between-ring domain provides insights for E3-ligase dysfunction in autosomal recessive Parkinson's disease [J].