D
IPR047535

E3 ubiquitin-protein ligase parkin, RING finger, HC subclass

InterPro entry
Short nameRING-HC_RBR_parkin
domain relationships

Description

This entry represents the RING domain found in parkin and similar proteins from animals. It is a C3HC4-type RING-HC finger required for RBR-mediated ubiquitination
[5]
.

E3 ubiquitin-protein ligase parkin, also called Parkinson juvenile disease protein 2, is an RBR-type E3 ubiquitin-protein ligase that is associated with recessive early onset Parkinson's disease (PD), and exerts a protective effect against dopamine-induced alpha-synuclein-dependent cell toxicity. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
[12]
. Parkin functions within a multiprotein E3 ubiquitin ligase complex, catalysing the covalent attachment of ubiquitin moieties onto substrate proteins, such as BCL2, SYT11, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPT5, TOMM20, USP30, ZNF746 and AIMP2
[1, 4]
. It mediates monoubiquitination as well as Lys6-, Lys11-, Lys48- and Lys63-linked polyubiquitination of substrates depending on the context
[9, 3, 6, 11]
. Parkin may enhance cell viability and protects dopaminergic neurons from oxidative stress-mediated death by regulating mitochondrial function
[8, 7]
. It also limits the production of reactive oxygen species (ROS), and regulates cyclin-E during neuronal apoptosis. Moreover, Parkin displays a ubiquitin ligase-independent function in transcriptional repression of p53
[12]
.

Parkin contains an N-terminal ubiquitin-like domain and a C-terminal RBR domain that was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction
[5, 10, 2]
.

References

1.Structure of Parkin Reveals Mechanisms for Ubiquitin Ligase Activation. Trempe JF, Sauve V, Grenier K, Seirafi M, Tang MY, Menade M, Al-Abdul-Wahid S, Krett J, Wong K, Kozlov G, Nagar B, Fon EA, Gehring K. Science (2013). PMID: 23661642

2.UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids. Wenzel DM, Lissounov A, Brzovic PS, Klevit RE. Nature 474, 105-8, (2011). View articlePMID: 21532592

3.USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria. Cunningham CN, Baughman JM, Phu L, Tea JS, Yu C, Coons M, Kirkpatrick DS, Bingol B, Corn JE. Nat Cell Biol 17, 160-9, (2015). PMID: 25621951

4.Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6. Olzmann JA, Li L, Chudaev MV, Chen J, Perez FA, Palmiter RD, Chin LS. J Cell Biol 178, 1025-38, (2007). PMID: 17846173

5.Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis. Kumar A, Aguirre JD, Condos TE, Martinez-Torres RJ, Chaugule VK, Toth R, Sundaramoorthy R, Mercier P, Knebel A, Spratt DE, Barber KR, Shaw GS, Walden H. EMBO J 34, 2506-21, (2015). PMID: 26254304

6.A Ubl/ubiquitin switch in the activation of Parkin. Sauve V, Lilov A, Seirafi M, Vranas M, Rasool S, Kozlov G, Sprules T, Wang J, Trempe JF, Gehring K. EMBO J 34, 2492-505, (2015). PMID: 26254305

7.A novel role for parkin in trauma-induced central nervous system secondary injury. Mukhida K, Kobayashi NR, Mendez I. Med Hypotheses 64, 1120-3, (2005). PMID: 15823698

8.Functional Role of Parkin against Oxidative Stress in Neural Cells. Hwang M, Lee JM, Kim Y, Geum D. Endocrinol Metab (Seoul) 29, 62-9, (2014). PMID: 24741456

9.PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K, Sarraf SA, Banerjee S, Youle RJ. J Cell Biol 205, 143-53, (2014). PMID: 24751536

10.Mechanism of phospho-ubiquitin-induced PARKIN activation. Wauer T, Simicek M, Schubert A, Komander D. Nature 524, 370-4, (2015). PMID: 26161729

11.Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. Imai Y, Soda M, Takahashi R. J Biol Chem 275, 35661-4, (2000). PMID: 10973942

12.Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease. da Costa CA, Sunyach C, Giaime E, West A, Corti O, Brice A, Safe S, Abou-Sleiman PM, Wood NW, Takahashi H, Goldberg MS, Shen J, Checler F. Nat Cell Biol 11, 1370-5, (2009). PMID: 19801972

Cross References

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