{"doi":"10.1101/2020.05.13.093849","title":"A new paradigm for Prelamin A proteolytic processing by ZMPSTE24: the upstream SY^LL cleavage occurs first and there is no CaaX processing by ZMPSTE24","abstract":"Abstract Human ZMPSTE24, an integral membrane zinc metalloprotease, is required for conversion of prelamin A to mature lamin A, a component of the nuclear lamina and failure of this processing causes premature ageing disorders. ZMPSTE24 has also been implicated in both type 2 diabetes mellitus and in viral-host response mechanisms, but to date its only confirmed substrate is the precursor for lamin A. Prelamin A is thought to undergo four C-terminal post-translational modifications in the following order: farnesylation, SIM tripeptide cleavage, carboxymethylation and upstream “SY^LL” cleavage. Here we present evidence that the sequence of events does not follow the accepted dogma. We assessed cleavage of long human prelamin A sequence peptides by purified human ZMPSTE24 combined with FRET and mass spectrometry to detect products. Surprisingly, we found that the “SY^LL” cleavage occurs before and independent of the C-terminal CSIM modifications. We also found that ZMPSTE24 does not perform the predicted C^SIM tripeptide cleavage, but rather it removes an IM dipeptide. ZMPSTE24 can perform a tripeptide cleavage with a canonical CaaX box (C: cysteine; a: aliphatic; X: any residue), but the C-terminus of prelamin A is not a true CaaX sequence. Regardless of the C-terminal modifications of prelamin A, ZMPSTE24 can perform upstream SY^LL cleavage, thus removing the unwanted farnesylated C-terminus. Therefore, it is failure of SY^LL cleavage, not the C-terminal processing that is the likely cause of progeroid disorders.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":120293,"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":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9539,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":437384,"name":"Eric D. Spear","orcid":"0000-0003-1980-0123","position":1,"is_corresponding":false},{"id":558197,"name":"Timothy D. Babatz","orcid":null,"position":2,"is_corresponding":false},{"id":557400,"name":"Andrew Quigley","orcid":"0000-0002-5022-9845","position":3,"is_corresponding":false},{"id":469950,"name":"Yin Yao Dong","orcid":"0000-0001-8600-6988","position":4,"is_corresponding":false},{"id":557401,"name":"Amy Chu","orcid":"0000-0003-4496-5616","position":5,"is_corresponding":false},{"id":558198,"name":"Bérénice Rotty","orcid":null,"position":6,"is_corresponding":false},{"id":557402,"name":"R. Chalk","orcid":"0000-0002-9942-2339","position":7,"is_corresponding":false},{"id":557403,"name":"Shubhashish Mukhopadhyay","orcid":"0000-0003-1430-5529","position":8,"is_corresponding":false},{"id":557404,"name":"N. Burgess-Brown","orcid":"0000-0003-0463-445X","position":9,"is_corresponding":false},{"id":557405,"name":"A.C.W. Pike","orcid":"0000-0001-9661-2607","position":10,"is_corresponding":false},{"id":268051,"name":"Stephen G. Young","orcid":"0000-0001-7270-3176","position":11,"is_corresponding":false},{"id":437388,"name":"Susan Michaelis","orcid":"0000-0001-5851-5021","position":12,"is_corresponding":false},{"id":558199,"name":"Elisabeth P. Carpenter","orcid":null,"position":13,"is_corresponding":false},{"id":558196,"name":"Laiyin Nie","orcid":null,"position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-18T23:14:33.640077Z","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":[]}