5ohp

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(New page: ==Crystal structure of USP30 (C77A) in complex with Lys6-linked diubiquitin== <StructureSection load='5ohp' size='340' side='right' caption='5ohp, resolution 2.80&Aring...)
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Revision as of 09:29, 4 October 2017

Crystal structure of USP30 (C77A) in complex with Lys6-linked diubiquitin

Structural highlights

5ohp is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	5ohk
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[UBP30_HUMAN] Deubiquitinating enzyme tethered to the mitochondrial outer membrane that acts as a key inhibitor of mitophagy by counteracting the action of parkin (PRKN): hydrolyzes ubiquitin attached by parkin on target proteins, such as RHOT1/MIRO1 and TOMM20, thereby blocking parkin's ability to drive mitophagy (PubMed:18287522, PubMed:24896179, PubMed:25527291, PubMed:25621951). Preferentially cleaves 'Lys-6'- and 'Lys-11'-linked polyubiquitin chains, 2 types of linkage that participate to mitophagic signaling (PubMed:25621951). Does not cleave efficiently polyubiquitin phosphorylated at 'Ser-65' (PubMed:25527291). Acts as negative regulator of mitochondrial fusion by mediating deubiquitination of MFN1 and MFN2 (By similarity).[UniProtKB:Q3UN04]^[1] ^[2] ^[3] ^[4] [UBB_HUMAN] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.^[5] ^[6]

Publication Abstract from PubMed

Damaged mitochondria undergo mitophagy, a specialized form of autophagy that is initiated by the protein kinase PINK1 and the ubiquitin E3 ligase Parkin. Ubiquitin-specific protease USP30 antagonizes Parkin-mediated ubiquitination events on mitochondria and is a key negative regulator of mitophagy. Parkin and USP30 both show a preference for assembly or disassembly, respectively, of Lys6-linked polyubiquitin, a chain type that has not been well studied. Here we report crystal structures of human USP30 bound to monoubiquitin and Lys6-linked diubiquitin, which explain how USP30 achieves Lys6-linkage preference through unique ubiquitin binding interfaces. We assess the interplay between USP30, PINK1 and Parkin and show that distally phosphorylated ubiquitin chains impair USP30 activity. Lys6-linkage-specific affimers identify numerous mitochondrial substrates for this modification, and we show that USP30 regulates Lys6-polyubiquitinated TOM20. Our work provides insights into the architecture, activity and regulation of USP30, which will aid drug design against this and related enzymes.

Mechanism and regulation of the Lys6-selective deubiquitinase USP30.,Gersch M, Gladkova C, Schubert AF, Michel MA, Maslen S, Komander D Nat Struct Mol Biol. 2017 Sep 25. doi: 10.1038/nsmb.3475. PMID:28945249^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Nakamura N, Hirose S. Regulation of mitochondrial morphology by USP30, a deubiquitinating enzyme present in the mitochondrial outer membrane. Mol Biol Cell. 2008 May;19(5):1903-11. Epub 2008 Feb 20. PMID:18287522 doi:http://dx.doi.org/E07-11-1103
↑ Bingol B, Tea JS, Phu L, Reichelt M, Bakalarski CE, Song Q, Foreman O, Kirkpatrick DS, Sheng M. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature. 2014 Jun 19;510(7505):370-5. doi: 10.1038/nature13418. Epub 2014 Jun 4. PMID:24896179 doi:http://dx.doi.org/10.1038/nature13418
↑ Wauer T, Swatek KN, Wagstaff JL, Gladkova C, Pruneda JN, Michel MA, Gersch M, Johnson CM, Freund SM, Komander D. Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain assembly and hydrolysis. EMBO J. 2014 Dec 19. pii: e201489847. PMID:25527291 doi:http://dx.doi.org/10.15252/embj.201489847
↑ Cunningham CN, Baughman JM, Phu L, Tea JS, Yu C, Coons M, Kirkpatrick DS, Bingol B, Corn JE. USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria. Nat Cell Biol. 2015 Feb;17(2):160-9. doi: 10.1038/ncb3097. Epub 2015 Jan 26. PMID:25621951 doi:http://dx.doi.org/10.1038/ncb3097
↑ Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell. 2006 Mar 17;21(6):737-48. PMID:16543144 doi:S1097-2765(06)00120-1
↑ Komander D. The emerging complexity of protein ubiquitination. Biochem Soc Trans. 2009 Oct;37(Pt 5):937-53. doi: 10.1042/BST0370937. PMID:19754430 doi:10.1042/BST0370937
↑ Gersch M, Gladkova C, Schubert AF, Michel MA, Maslen S, Komander D. Mechanism and regulation of the Lys6-selective deubiquitinase USP30. Nat Struct Mol Biol. 2017 Sep 25. doi: 10.1038/nsmb.3475. PMID:28945249 doi:http://dx.doi.org/10.1038/nsmb.3475