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

Riley, B. E.; Lougheed, J. C.; Callaway, K.; Velasquez, M.; Brecht, E.; Nguyen, L.; Shaler, T.; Walker, D.; Yang, Y.; Regnstrom, K.; Diep, L.; Zhang, Z.; Chiou, S.; Bova, M.; Artis, D. R.; Yao, N.; Baker, J.; Yednock, T.; Johnston, J. A.

doi:10.1038/ncomms2982

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

Journal Article · Mon Jun 17 00:00:00 EDT 2013 · Nature Communications

DOI:https://doi.org/10.1038/ncomms2982· OSTI ID:1623913

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]

Elan Pharmaceuticals, South San Francisco, CA (United States)
SRI International, Menlo Park, CA (United States)

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 Å 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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1623913

Journal Information:: Nature Communications, Vol. 4, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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RING-Domain E3 Ligase-Mediated Host–Virus Interactions: Orchestrating Immune Responses by the Host and Antagonizing Immune Defense by Viruses Zhang, Yuexiu; Li, Lian-Feng; Munir, Muhammad Frontiers in Immunology, Vol. 9 https://doi.org/10.3389/fimmu.2018.01083	journal	May 2018
Will Crystal Parkin Help in Understanding the Future of Parkinsonâ€™s Disease? Olszewska, Diana Angelika; Lynch, Tim Frontiers in Neurology, Vol. 6 https://doi.org/10.3389/fneur.2015.00035	journal	February 2015
The Transcription Factor Function of Parkin: Breaking the Dogma Alves da Costa, Cristine; Duplan, Eric; Rouland, Lila Frontiers in Neuroscience, Vol. 12 https://doi.org/10.3389/fnins.2018.00965	journal	January 2019
Molecular dynamics simulations of human E3 ubiquitin ligase Parkin Qiu, Shi; Zhu, Shun; Xu, Shan Molecular Medicine Reports, Vol. 16, Issue 4 https://doi.org/10.3892/mmr.2017.7140	journal	August 2017

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