{"doi":"10.1098/rsob.160193","title":"Covalent ISG15 conjugation positively regulates the ubiquitin E3 ligase activity of parkin","abstract":"<jats:p>\n            Parkinson's disease (PD) is characterized by selective loss of dopaminergic neurons in the pars compacta of the substantia nigra and accumulation of ubiquitinated proteins in aggregates called Lewy bodies. Several mutated genes have been found in familial PD patients, including\n            <jats:italic>SNCA</jats:italic>\n            (α-synuclein),\n            <jats:italic>PARK2</jats:italic>\n            (parkin),\n            <jats:italic>PINK1</jats:italic>\n            ,\n            <jats:italic>PARK7</jats:italic>\n            (DJ-1),\n            <jats:italic>LRRK2</jats:italic>\n            and\n            <jats:italic>ATP13A2</jats:italic>\n            . Many pathogenic mutations of\n            <jats:italic>PARK2</jats:italic>\n            , which encodes the ubiquitin E3 ligase parkin, result in loss of function, leading to accumulation of parkin substrates and consequently contributing to dopaminergic cell death. ISG15 is a member of the ubiquitin-like modifier family and is induced by stimulation with type I interferons. Similar to ubiquitin and ubiquitination, covalent conjugation of ISG15 to target proteins (ISGylation) regulates their biochemical properties. In this study, we identified parkin as a novel target of ISGylation specifically mediated by the ISG15-E3 ligase HERC5. In addition, we identified two ISGylation sites, Lys-349 and Lys-369, in the in-between-ring domain of parkin. ISGylation of these sites promotes parkin's ubiquitin E3 ligase activity by suppressing the intramolecular interaction that maintains its autoinhibited conformation and increases its cytoprotective effect. In conclusion, covalent ISG15 conjugation is a novel mode of modulating parkin activity, and alteration in this pathway may be associated with PD pathogenesis.\n          </jats:p>","journal":"Open Biology","year":2016,"id":602970,"datarank":0.6038027536102726,"base_score":4.02535169073515,"endowment":4.02535169073515,"self_citation_contribution":0.6038027536102726,"citation_network_contribution":0.0,"self_endowment_contribution":0.6038027536102726,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":55,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":890934,"name":"Lang Yoo","orcid":null,"position":1,"is_corresponding":false},{"id":1546643,"name":"Minju Hyun","orcid":null,"position":2,"is_corresponding":false},{"id":1546644,"name":"Woo Hyun Shin","orcid":null,"position":3,"is_corresponding":false},{"id":1546645,"name":"Kwang Chul Chung","orcid":"0000-0003-4658-3849","position":4,"is_corresponding":false},{"id":806663,"name":"Eunju Im","orcid":"0000-0002-7839-8878","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Covalent ISG15 conjugation positively regulates the ubiquitin E3 ligase activity of parkin","abstract":"<jats:p>\n            Parkinson's disease (PD) is characterized by selective loss of dopaminergic neurons in the pars compacta of the substantia nigra and accumulation of ubiquitinated proteins in aggregates called Lewy bodies. Several mutated genes have been found in familial PD patients, including\n            <jats:italic>SNCA</jats:italic>\n            (α-synuclein),\n            <jats:italic>PARK2</jats:italic>\n            (parkin),\n            <jats:italic>PINK1</jats:italic>\n            ,\n            <jats:italic>PARK7</jats:italic>\n            (DJ-1),\n            <jats:italic>LRRK2</jats:italic>\n            and\n            <jats:italic>ATP13A2</jats:italic>\n            . Many pathogenic mutations of\n            <jats:italic>PARK2</jats:italic>\n            , which encodes the ubiquitin E3 ligase parkin, result in loss of function, leading to accumulation of parkin substrates and consequently contributing to dopaminergic cell death. ISG15 is a member of the ubiquitin-like modifier family and is induced by stimulation with type I interferons. Similar to ubiquitin and ubiquitination, covalent conjugation of ISG15 to target proteins (ISGylation) regulates their biochemical properties. In this study, we identified parkin as a novel target of ISGylation specifically mediated by the ISG15-E3 ligase HERC5. In addition, we identified two ISGylation sites, Lys-349 and Lys-369, in the in-between-ring domain of parkin. ISGylation of these sites promotes parkin's ubiquitin E3 ligase activity by suppressing the intramolecular interaction that maintains its autoinhibited conformation and increases its cytoprotective effect. In conclusion, covalent ISG15 conjugation is a novel mode of modulating parkin activity, and alteration in this pathway may be associated with PD pathogenesis.\n          </jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"27534820","pmcid":null,"openalex_id":null,"authors":[],"funders":[{"funder_name":"Yonsei University Future-leading Research Initiative of 2015","grant_id":"2015-22-0055","title":null},{"funder_name":"Yonsei University Research Fund of 2014","grant_id":"2014-12-0134","title":null},{"funder_name":"Korea Health Industry Development Institute","grant_id":"HI14C0093","title":null},{"funder_name":"National Research Foundation of Korea","grant_id":"2014M3C7A1064545","title":null},{"funder_name":"National Research Foundation of Korea","grant_id":"2015R1A2A2A01003080","title":null}],"total_grants":5,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1098/rsob.160193","host_type":"publisher"},{"url":"https://royalsocietypublishing.org/doi/pdf/10.1098/rsob.160193","host_type":"publisher"},{"url":"https://royalsocietypublishing.org/doi/full-xml/10.1098/rsob.160193","host_type":"publisher"},{"url":"https://doaj.org/article/45226923eddb450488a4d3cce334b380","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/5008018","host_type":"repository"}],"fields_of_study":["Animals","Binding Sites","COS Cells","Cell Line","Chlorocebus aethiops","Cytokines","HEK293 Cells","HeLa Cells","Humans","Intracellular Signaling Peptides and Proteins","Lysine","Mice","Mutation, Missense","NIH 3T3 Cells","Parkinson Disease","Ubiquitin-Protein Ligases","Ubiquitins"],"mesh_terms":["Animals","Binding Sites","COS Cells","Cell Line","Chlorocebus aethiops","Cytokines","HEK293 Cells","HeLa Cells","Humans","Intracellular Signaling Peptides and Proteins","Lysine","Mice","Mutation, Missense","NIH 3T3 Cells","Parkinson Disease","Ubiquitin-Protein Ligases","Ubiquitins"],"keywords":["E3 ligase","HERC5","ISG15","ISGylation","Parkinson's disease","parkin"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-29T20:46:58.147932Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}