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Cited by 558

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids

Open access
Wenzel, Dawn M., Lissounov, Alexei, Brzovic, Peter S., Klevit, Rachel E.·2011·Nature
DOI 10.1038/nature09966
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Abstract

Although the functional interaction between ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s) is essential in ubiquitin (Ub) signalling, the criteria that define an active E2–E3 pair are not well established. The human E2 UBCH7 (also known as UBE2L3) shows broad specificity for HECT-type E3s, but often fails to function with RING E3s in vitro despite forming specific complexes. Structural comparisons of inactive UBCH7–RING complexes with active UBCH5–RING complexes reveal no defining differences, highlighting a gap in our understanding of Ub transfer. Here we show that, unlike many E2s that transfer Ub with RINGs, UBCH7 lacks intrinsic, E3-independent reactivity with lysine, explaining its preference for HECTs. Despite lacking lysine reactivity, UBCH7 exhibits activity with the RING-in-between-RING (RBR) family of E3s that includes parkin (also known as PARK2) and human homologue of ariadne (HHARI; also known as ARIH1). Found in all eukaryotes, RBRs regulate processes such as translation and immune signalling. RBRs contain a canonical C3HC4-type RING, followed by two conserved Cys/His-rich Zn2+-binding domains, in-between-RING (IBR) and RING2 domains, which together define this E3 family. We show that RBRs function like RING/HECT hybrids: they bind E2s via a RING domain, but transfer Ub through an obligate thioester-linked Ub (denoted ∼Ub), requiring a conserved cysteine residue in RING2. Our results define the functional cadre of E3s for UBCH7, an E2 involved in cell proliferation and immune function, and indicate a novel mechanism for an entire class of E3s.

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Citations

Cites

  • Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase

    Shimura, H., Hattori, N., Kubo, S.-I., Mizuno, Y., Asakawa, S., Minoshima, S., Shimizu, N., Iwai, K., Chiba, T., Tanaka, K., et al. (2000) · Nature Genetics · doi:10.1038/77060 · Cited by 2,024 · cited 1×

    “In matched experiments with UbcH7, neither BRCA1/BARD1 nor E6AP enhance reactivity toward free cysteine (Supplementary Fig 8a, c.) Besides HECT-type ligases, UbcH7 is reported to function with members of the RING E3 family known as RBRs that includes Parkin and HHARI 5,6 .”

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Metadata

Authors
Wenzel, D. M., Lissounov, A., Brzovic, P. S., & Klevit, R. E.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2011-05-01
Volume
474
Issue
7349
Pages
105-108
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature09966
OpenAlex
W1983470920
Cited by
558
References
1
FWCI
15.99
Type
journal article
Language
en
Open access
green

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