Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases
| Autor: | D.R. Artis, J.A. Johnston, J.C. Lougheed, K. Callaway, B.E. Riley, Michael P. Bova, Z. Zhang, E. Brecht, N.H. Yao, J. Baker, D. Walker, L. Diep, M. Velasquez, Lan K. Nguyen, S. Chiou, Y. Yang, T. Yednock, Thomas A. Shaler, K. Regnstrom |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Phenylalanine Ubiquitin-Protein Ligases General Physics and Astronomy Biology Mitochondrion medicine.disease_cause General Biochemistry Genetics and Molecular Biology Parkin Article 03 medical and health sciences 0302 clinical medicine Protein structure Catalytic Domain medicine Humans 030304 developmental biology chemistry.chemical_classification 0303 health sciences DNA ligase Mutation Multidisciplinary Parkinson Disease General Chemistry 3. Good health Ubiquitin ligase Cell biology nervous system diseases Mitochondria Protein Structure Tertiary Enzyme Biochemistry chemistry biology.protein Biocatalysis 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. The Parkinson’s disease-associated protein Parkin regulates the fate of damaged mitochondria by ubiquitinating mitochondrial substrates. Riley et al. present the crystal structure of the Parkin-R0RBR domain, providing new insight into the catalytic mechanism of the enzyme. |
| Databáze: | OpenAIRE |
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