{"doi":"10.1016/j.jbc.2021.100902","title":"Effect of clinical isolate or cleavage site mutations in the SARS-CoV-2 spike protein on protein stability, cleavage, and cell–cell fusion","abstract":"The trimeric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S) is the sole viral protein responsible for both viral binding to a host cell and the membrane fusion event needed for cell entry. In addition to facilitating fusion needed for viral entry, S can also drive cell-cell fusion, a pathogenic effect observed in the lungs of SARS-CoV-2-infected patients. While several studies have investigated S requirements involved in viral particle entry, examination of S stability and factors involved in S cell-cell fusion remain limited. A furin cleavage site at the border between the S1 and S2 subunits (S1/S2) has been identified, along with putative cathepsin L and transmembrane serine protease 2 cleavage sites within S2. We demonstrate that S must be processed at the S1/S2 border in order to mediate cell-cell fusion and that mutations at potential cleavage sites within the S2 subunit alter S processing at the S1/S2 border, thus preventing cell-cell fusion. We also identify residues within the internal fusion peptide and the cytoplasmic tail that modulate S-mediated cell-cell fusion. In addition, we examined S stability and protein cleavage kinetics in a variety of mammalian cell lines, including a bat cell line related to the likely reservoir species for SARS-CoV-2, and provide evidence that proteolytic processing alters the stability of the S trimer. This work therefore offers insight into S stability, proteolytic processing, and factors that mediate S cell-cell fusion, all of which help give a more comprehensive understanding of this high-profile therapeutic target.","journal":"Journal of Biological Chemistry","year":2021,"id":171762,"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":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9586,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":706675,"name":"Hadley E. Neal","orcid":"0000-0001-8433-593X","position":1,"is_corresponding":false},{"id":707174,"name":"Kearstin Edmonds","orcid":null,"position":2,"is_corresponding":false},{"id":707175,"name":"Carole L. Moncman","orcid":null,"position":3,"is_corresponding":false},{"id":706676,"name":"Rachel Thompson","orcid":"0000-0001-6332-545X","position":4,"is_corresponding":false},{"id":707176,"name":"Jean Mawuena Branttie","orcid":null,"position":5,"is_corresponding":false},{"id":707177,"name":"Kerri Beth Boggs","orcid":null,"position":6,"is_corresponding":false},{"id":706677,"name":"Cheng‐Yu Wu","orcid":"0000-0003-4088-6347","position":7,"is_corresponding":false},{"id":328258,"name":"Daisy W. Leung","orcid":"0000-0002-7189-9557","position":8,"is_corresponding":false},{"id":300660,"name":"Rebecca Dutch","orcid":"0000-0002-5220-8247","position":9,"is_corresponding":false},{"id":303005,"name":"Chelsea T. Barrett","orcid":null,"position":0,"is_corresponding":true}],"reference_count":125,"raw_metadata":null,"created_at":"2026-07-18T23:46:33.067299Z","pmid":"34157282","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":[]}