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


ABSTRACT: 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.

SUBMITTER: Riley BE 

PROVIDER: S-EPMC3709503 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

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

Nature communications 20130101


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 arc  ...[more]

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