{"doi":"10.1126/sciadv.abj8633","title":"Cln5 represents a new type of cysteine-based <i>S</i> -depalmitoylase linked to neurodegeneration","abstract":"Genetic CLN5 variants are associated with childhood neurodegeneration and Alzheimer’s disease; however, the molecular function of ceroid lipofuscinosis neuronal protein 5 (Cln5) is unknown. We solved the Cln5 crystal structure and identified a region homologous to the catalytic domain of members of the N1pC/P60 superfamily of papain-like enzymes. However, we observed no protease activity for Cln5; and instead, we discovered that Cln5 and structurally related PPPDE1 and PPPDE2 have efficient cysteine palmitoyl thioesterase ( S -depalmitoylation) activity using fluorescent substrates. Mutational analysis revealed that the predicted catalytic residues histidine-166 and cysteine-280 are critical for Cln5 thioesterase activity, uncovering a new cysteine-based catalytic mechanism for S -depalmitoylation enzymes. Last, we found that Cln5-deficient neuronal progenitor cells showed reduced thioesterase activity, confirming live cell function of Cln5 in setting S -depalmitoylation levels. Our results provide new insight into the function of Cln5, emphasize the importance of S -depalmitoylation in neuronal homeostasis, and disclose a new, unexpected enzymatic function for the N1pC/P60 superfamily of proteins.","journal":"Science Advances","year":2022,"id":249826,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9614,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":890677,"name":"Daniel A. Bender","orcid":"0000-0002-2975-4186","position":1,"is_corresponding":false},{"id":471014,"name":"Stefan Becker","orcid":"0000-0003-2041-5740","position":2,"is_corresponding":false},{"id":890678,"name":"Lisa M. Crowther","orcid":"0000-0002-8640-3884","position":3,"is_corresponding":false},{"id":890679,"name":"Ilka Erven","orcid":"0000-0002-1095-6861","position":4,"is_corresponding":false},{"id":90539,"name":"Kay Hofmann","orcid":"0000-0002-2289-9083","position":5,"is_corresponding":false},{"id":262432,"name":"Johannes Söding","orcid":"0000-0001-9642-8244","position":6,"is_corresponding":false},{"id":890680,"name":"Henry Gerd Klemp","orcid":"0000-0002-3147-3017","position":7,"is_corresponding":false},{"id":890681,"name":"Cristina Bellotti","orcid":"0000-0002-3999-2807","position":8,"is_corresponding":false},{"id":890682,"name":"Andreas Stäuble","orcid":"0000-0001-9691-1690","position":9,"is_corresponding":false},{"id":822615,"name":"Tian Qiu","orcid":"0000-0002-7168-0715","position":10,"is_corresponding":false},{"id":551846,"name":"Rahul S. Kathayat","orcid":"0000-0002-9159-2413","position":11,"is_corresponding":false},{"id":551852,"name":"Bryan C. Dickinson","orcid":"0000-0002-9616-1911","position":12,"is_corresponding":false},{"id":387823,"name":"Jutta Gärtner","orcid":"0000-0003-4108-7109","position":13,"is_corresponding":false},{"id":34380,"name":"George M. Sheldrick","orcid":"0000-0001-6956-4822","position":14,"is_corresponding":false},{"id":891171,"name":"Ralph Krätzner","orcid":null,"position":15,"is_corresponding":false},{"id":503415,"name":"Robert Steinfeld","orcid":"0000-0003-0956-6601","position":16,"is_corresponding":false},{"id":890676,"name":"Anna V. Luebben","orcid":"0000-0003-2867-9468","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T00:24:23.754337Z","pmid":"35427157","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":[]}