| Structural highlights
Function
PRKN_DROME E3 ubiquitin-protein ligase which accepts ubiquitin from E2 ubiquitin-conjugating enzymes in the form of a thioester and then directly transfers the ubiquitin to targeted substrates, such as Paris, Marf, Opa1, Miro, pnut, Septin1, Tom20 and porin (PubMed:16002472, PubMed:17456438, PubMed:25474007, PubMed:20194754, PubMed:24192653, PubMed:24901221, PubMed:27906179, PubMed:31714929, PubMed:32138754, PubMed:32047033, PubMed:23770917). Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates, depending on the context (PubMed:18957282, PubMed:24901221, PubMed:25474007, PubMed:23650379, PubMed:27906179, PubMed:31714929, PubMed:32047033). Protects against mitochondrial dysfunction during cellular stress, by acting downstream of Pink1, to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components (PubMed:12642658, PubMed:15073152, PubMed:16672980, PubMed:16672981, PubMed:17123504, PubMed:18957282, PubMed:18799731, PubMed:18230723, PubMed:18443288, PubMed:20496123, PubMed:20194754, PubMed:23509287, PubMed:24192653, PubMed:24901221, PubMed:25474007, PubMed:27906179, PubMed:29497364, PubMed:32047033). Depending on the severity of mitochondrial damage and/or dysfunction, activity ranges from preventing apoptosis and stimulating mitochondrial biogenesis to regulating mitochondrial dynamics and eliminating severely damaged mitochondria via mitophagy (PubMed:12642658, PubMed:15073152, PubMed:16002472, PubMed:16672980, PubMed:16672981, PubMed:17123504, PubMed:18957282, PubMed:18799731, PubMed:18230723, PubMed:18443288, PubMed:20496123, PubMed:20194754, PubMed:23509287, PubMed:24192653, PubMed:24901221, PubMed:25474007, PubMed:27906179, PubMed:29497364, PubMed:32047033). Appears to be particularly important in maintaining the physiology and function of cells with high energy demands that are undergoing stress or altered metabolic environment, including spermatids, muscle cells and neurons such as the dopaminergic (DA) neurons (PubMed:12642658, PubMed:15073152, PubMed:16002472, PubMed:16672980, PubMed:17123504, PubMed:18799731, PubMed:20483372, PubMed:22396657, PubMed:24901221, PubMed:28435104, PubMed:29497364, PubMed:31714929). Activation and recruitment onto the outer membrane of damaged/dysfunctional mitochondria (OMM) requires Pink1-mediated phosphorylation of both park and ubiquitin (PubMed:18957282, PubMed:24901221, PubMed:20194754, PubMed:22396657, PubMed:18799731, PubMed:18230723, PubMed:25474007, PubMed:27906179). In depolarized mitochondria, mediates the decision between mitophagy or preventing apoptosis by inducing either the poly- or monoubiquitination of porin/VDAC; polyubiquitination of porin promotes mitophagy, while monoubiquitination of porin decreases mitochondrial calcium influx which ultimately inhibits apoptosis (PubMed:32047033). When cellular stress results in irreversible mitochondrial damage, promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins (PubMed:16672980, PubMed:16672981, PubMed:20194754, PubMed:18957282, PubMed:23509287, PubMed:24192653, PubMed:25474007, PubMed:29497364). Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains following mitochondrial damage, leading to mitophagy (PubMed:32047033, PubMed:23650379). In developing tissues, inhibits JNK-mediated apoptosis by negatively regulating bsk transcription (PubMed:16002472, PubMed:20496123). The Pink1-park pathway also promotes fission and/or inhibits fusion of damaged mitochondria by mediating the ubiquitination and subsequent degradation of proteins involved in mitochondrial fusion/fission such as Marf, Opa1 and fzo (PubMed:18443288, PubMed:17123504, PubMed:18799731, PubMed:18230723, PubMed:20194754, PubMed:23650379, PubMed:24192653, PubMed:24901221, PubMed:29497364). This prevents the refusion of unhealthy mitochondria with the healthy mitochondrial network and/or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes (PubMed:18443288, PubMed:17123504, PubMed:18799731, PubMed:18230723, PubMed:20194754, PubMed:23650379, PubMed:24192653, PubMed:24901221, PubMed:29497364). Regulates motility of damaged mitochondria by phosphorylating Miro which likely promotes its park-dependent degradation by the proteasome; in motor neurons, this inhibits mitochondrial intracellular anterograde transport along the axons which probably increases the chance of the mitochondria being eliminated in the soma (PubMed:22396657). The Pink1-park pathway is also involved in mitochondrial regeneration processes such as promoting mitochondrial biogenesis, activating localized mitochondrial repair, promoting selective turnover of mitochondrial proteins and initiating the mitochondrial import of endogenous proteins (PubMed:16672980, PubMed:20496123, PubMed:20869429, PubMed:23509287, PubMed:23650379, PubMed:24192653, PubMed:25565208, PubMed:29497364). Involved in mitochondrial biogenesis via the ubiquitination of transcriptional repressor Paris which leads to its subsequent proteasomal degradation and allows activation of the transcription factor srl (PubMed:23509287, PubMed:29497364, PubMed:32138754). Promotes localized mitochondrial repair by activating the translation of specific nuclear-encoded mitochondrial RNAs (nc-mtRNAs) on the mitochondrial surface, including several key electron transport chain component nc-mtRNAs (PubMed:23509287, PubMed:25565208).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29]
Publication Abstract from PubMed
Mutations in the park2 gene, encoding the RING-inBetweenRING-RING E3 ubiquitin ligase parkin, cause 50% of autosomal recessive juvenile Parkinsonism cases. More than 70 known pathogenic mutations occur throughout parkin, many of which cluster in the inhibitory amino-terminal ubiquitin-like domain, and the carboxy-terminal RING2 domain that is indispensable for ubiquitin transfer. A structural rationale showing how autosomal recessive juvenile Parkinsonism mutations alter parkin function is still lacking. Here we show that the structure of parkin RING2 is distinct from canonical RING E3 ligases and lacks key elements required for E2-conjugating enzyme recruitment. Several pathogenic mutations in RING2 alter the environment of a single surface-exposed catalytic cysteine to inhibit ubiquitination. Native parkin adopts a globular inhibited conformation in solution facilitated by the association of the ubiquitin-like domain with the RING-inBetweenRING-RING C-terminus. Autosomal recessive juvenile Parkinsonism mutations disrupt this conformation. Finally, parkin autoubiquitinates only in cis, providing a molecular explanation for the recessive nature of autosomal recessive juvenile Parkinsonism.
A molecular explanation for the recessive nature of parkin-linked Parkinson's disease.,Spratt DE, Julio Martinez-Torres R, Noh YJ, Mercier P, Manczyk N, Barber KR, Aguirre JD, Burchell L, Purkiss A, Walden H, Shaw GS Nat Commun. 2013 Jun 17;4:1983. doi: 10.1038/ncomms2983. PMID:23770917[30]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Greene JC, Whitworth AJ, Kuo I, Andrews LA, Feany MB, Pallanck LJ. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4078-83. PMID:12642658 doi:10.1073/pnas.0737556100
- ↑ Pesah Y, Pham T, Burgess H, Middlebrooks B, Verstreken P, Zhou Y, Harding M, Bellen H, Mardon G. Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development. 2004 May;131(9):2183-94. PMID:15073152 doi:10.1242/dev.01095
- ↑ Cha GH, Kim S, Park J, Lee E, Kim M, Lee SB, Kim JM, Chung J, Cho KS. Parkin negatively regulates JNK pathway in the dopaminergic neurons of Drosophila. Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10345-50. PMID:16002472 doi:10.1073/pnas.0500346102
- ↑ Park J, Lee SB, Lee S, Kim Y, Song S, Kim S, Bae E, Kim J, Shong M, Kim JM, Chung J. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature. 2006 Jun 29;441(7097):1157-61. PMID:16672980 doi:10.1038/nature04788
- ↑ Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH, Yoo SJ, Hay BA, Guo M. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature. 2006 Jun 29;441(7097):1162-6. PMID:16672981 doi:10.1038/nature04779
- ↑ Riparbelli MG, Callaini G. The Drosophila parkin homologue is required for normal mitochondrial dynamics during spermiogenesis. Dev Biol. 2007 Mar 1;303(1):108-20. PMID:17123504 doi:10.1016/j.ydbio.2006.10.038
- ↑ Bae YJ, Kang SJ, Park KS. Drosophila melanogaster Parkin ubiquitinates peanut and septin1 as an E3 ubiquitin-protein ligase. Insect Biochem Mol Biol. 2007 May;37(5):430-9. doi: 10.1016/j.ibmb.2007.01.007. , Epub 2007 Feb 12. PMID:17456438 doi:http://dx.doi.org/10.1016/j.ibmb.2007.01.007
- ↑ Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ, Pallanck LJ. The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43. PMID:18230723 doi:10.1073/pnas.0709336105
- ↑ Yang Y, Ouyang Y, Yang L, Beal MF, McQuibban A, Vogel H, Lu B. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Natl Acad Sci U S A. 2008 May 13;105(19):7070-5. PMID:18443288 doi:10.1073/pnas.0711845105
- ↑ Deng H, Dodson MW, Huang H, Guo M. The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14503-8. PMID:18799731 doi:10.1073/pnas.0803998105
- ↑ Kim Y, Park J, Kim S, Song S, Kwon SK, Lee SH, Kitada T, Kim JM, Chung J. PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem Biophys Res Commun. 2008 Dec 19;377(3):975-80. PMID:18957282 doi:10.1016/j.bbrc.2008.10.104
- ↑ Ziviani E, Tao RN, Whitworth AJ. Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5018-23. PMID:20194754 doi:10.1073/pnas.0913485107
- ↑ Saini N, Oelhafen S, Hua H, Georgiev O, Schaffner W, Büeler H. Extended lifespan of Drosophila parkin mutants through sequestration of redox-active metals and enhancement of anti-oxidative pathways. Neurobiol Dis. 2010 Oct;40(1):82-92. PMID:20483372 doi:10.1016/j.nbd.2010.05.011
- ↑ Hwang S, Kim D, Choi G, An SW, Hong YK, Suh YS, Lee MJ, Cho KS. Parkin suppresses c-Jun N-terminal kinase-induced cell death via transcriptional regulation in Drosophila. Mol Cells. 2010 Jun;29(6):575-80. PMID:20496123 doi:10.1007/s10059-010-0068-1
- ↑ Ottone C, Galasso A, Gemei M, Pisa V, Gigliotti S, Piccioni F, Graziani F, Verrotti di Pianella A. Diminution of eIF4E activity suppresses parkin mutant phenotypes. Gene. 2011 Jan 1;470(1-2):12-9. PMID:20869429 doi:10.1016/j.gene.2010.09.003
- ↑ Liu S, Sawada T, Lee S, Yu W, Silverio G, Alapatt P, Millan I, Shen A, Saxton W, Kanao T, Takahashi R, Hattori N, Imai Y, Lu B. Parkinson's disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria. PLoS Genet. 2012;8(3):e1002537. PMID:22396657 doi:10.1371/journal.pgen.1002537
- ↑ Vincow ES, Merrihew G, Thomas RE, Shulman NJ, Beyer RP, MacCoss MJ, Pallanck LJ. The PINK1-Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo. Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6400-5. PMID:23509287 doi:10.1073/pnas.1221132110
- ↑ Rana A, Rera M, Walker DW. Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan. Proc Natl Acad Sci U S A. 2013 May 21;110(21):8638-43. PMID:23650379 doi:10.1073/pnas.1216197110
- ↑ Spratt DE, Julio Martinez-Torres R, Noh YJ, Mercier P, Manczyk N, Barber KR, Aguirre JD, Burchell L, Purkiss A, Walden H, Shaw GS. A molecular explanation for the recessive nature of parkin-linked Parkinson's disease. Nat Commun. 2013 Jun 17;4:1983. doi: 10.1038/ncomms2983. PMID:23770917 doi:10.1038/ncomms2983
- ↑ Bhandari P, Song M, Chen Y, Burelle Y, Dorn GW 2nd. Mitochondrial contagion induced by Parkin deficiency in Drosophila hearts and its containment by suppressing mitofusin. Circ Res. 2014 Jan 17;114(2):257-65. doi: 10.1161/CIRCRESAHA.114.302734. Epub , 2013 Nov 5. PMID:24192653 doi:http://dx.doi.org/10.1161/CIRCRESAHA.114.302734
- ↑ Shiba-Fukushima K, Inoshita T, Hattori N, Imai Y. PINK1-mediated phosphorylation of Parkin boosts Parkin activity in Drosophila. PLoS Genet. 2014 Jun 5;10(6):e1004391. PMID:24901221 doi:10.1371/journal.pgen.1004391
- ↑ Shiba-Fukushima K, Arano T, Matsumoto G, Inoshita T, Yoshida S, Ishihama Y, Ryu KY, Nukina N, Hattori N, Imai Y. Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin mitochondrial tethering. PLoS Genet. 2014 Dec 4;10(12):e1004861. doi: 10.1371/journal.pgen.1004861. , eCollection 2014 Dec. PMID:25474007 doi:http://dx.doi.org/10.1371/journal.pgen.1004861
- ↑ Gehrke S, Wu Z, Klinkenberg M, Sun Y, Auburger G, Guo S, Lu B. PINK1 and Parkin control localized translation of respiratory chain component mRNAs on mitochondria outer membrane. Cell Metab. 2015 Jan 6;21(1):95-108. PMID:25565208 doi:10.1016/j.cmet.2014.12.007
- ↑ Zhuang N, Li L, Chen S, Wang T. PINK1-dependent phosphorylation of PINK1 and Parkin is essential for mitochondrial quality control. Cell Death Dis. 2016 Dec 1;7(12):e2501. PMID:27906179 doi:10.1038/cddis.2016.396
- ↑ Julienne H, Buhl E, Leslie DS, Hodge JJL. Drosophila PINK1 and parkin loss-of-function mutants display a range of non-motor Parkinson's disease phenotypes. Neurobiol Dis. 2017 Aug;104:15-23. PMID:28435104 doi:10.1016/j.nbd.2017.04.014
- ↑ Cackovic J, Gutierrez-Luke S, Call GB, Juba A, O'Brien S, Jun CH, Buhlman LM. Vulnerable Parkin Loss-of-Function Drosophila Dopaminergic Neurons Have Advanced Mitochondrial Aging, Mitochondrial Network Loss and Transiently Reduced Autophagosome Recruitment. Front Cell Neurosci. 2018 Feb 15;12:39. PMID:29497364 doi:10.3389/fncel.2018.00039
- ↑ Si H, Ma P, Liang Q, Yin Y, Wang P, Zhang Q, Wang S, Deng H. Overexpression of pink1 or parkin in indirect flight muscles promotes mitochondrial proteostasis and extends lifespan in Drosophila melanogaster. PLoS One. 2019 Nov 12;14(11):e0225214. PMID:31714929 doi:10.1371/journal.pone.0225214
- ↑ Ham SJ, Lee D, Yoo H, Jun K, Shin H, Chung J. Decision between mitophagy and apoptosis by Parkin via VDAC1 ubiquitination. Proc Natl Acad Sci U S A. 2020 Feb 25;117(8):4281-4291. doi: , 10.1073/pnas.1909814117. Epub 2020 Feb 11. PMID:32047033 doi:http://dx.doi.org/10.1073/pnas.1909814117
- ↑ Pirooznia SK, Yuan C, Khan MR, Karuppagounder SS, Wang L, Xiong Y, Kang SU, Lee Y, Dawson VL, Dawson TM. PARIS induced defects in mitochondrial biogenesis drive dopamine neuron loss under conditions of parkin or PINK1 deficiency. Mol Neurodegener. 2020 Mar 5;15(1):17. PMID:32138754 doi:10.1186/s13024-020-00363-x
- ↑ Spratt DE, Julio Martinez-Torres R, Noh YJ, Mercier P, Manczyk N, Barber KR, Aguirre JD, Burchell L, Purkiss A, Walden H, Shaw GS. A molecular explanation for the recessive nature of parkin-linked Parkinson's disease. Nat Commun. 2013 Jun 17;4:1983. doi: 10.1038/ncomms2983. PMID:23770917 doi:10.1038/ncomms2983
|
