{"doi":"10.1101/2022.04.11.487882","title":"Receptor binding domain of SARS-CoV-2 is a functional αv-integrin agonist","abstract":"ABSTRACT Among the novel mutations distinguishing SARS-CoV-2 from similar respiratory coronaviruses is a K403R substitution in the receptor-binding domain (RBD) of the viral spike (S) protein within its S1 region. This amino acid substitution occurs near the angiotensin-converting enzyme 2 (ACE2)-binding interface and gives rise to a canonical RGD adhesion motif that is often found in native extracellular matrix proteins, including fibronectin. In the present study, the ability of recombinant S1-RBD to bind to cell surface integrins and trigger downstream signaling pathways was assessed and compared to RGD-containing, integrin-binding fragments of fibronectin. S1-RBD supported adhesion of both fibronectin-null mouse embryonic fibroblasts as well as primary human small airway epithelial cells. Cell adhesion to S1-RBD was cation- and RGD-dependent, and was inhibited by blocking antibodies against α v and β 3 , but not α 5 or β 1 , integrins. Similarly, direct binding of S1-RBD to recombinant human α v β 3 and α v β 6 integrins, but not α 5 β 1 integrins, was observed by surface plasmon resonance. Adhesion to S1-RBD initiated cell spreading, focal adhesion formation, and actin stress fiber organization to a similar extent as fibronectin. Moreover, S1-RBD stimulated tyrosine phosphorylation of the adhesion mediators FAK, Src, and paxillin, Akt activation, and supported cell proliferation. Together, these data demonstrate that the RGD sequence within S1-RBD can function as an α v -selective integrin agonist. This study provides evidence that cell surface α v -containing integrins can respond functionally to spike protein and raise the possibility that S1-mediated dysregulation of ECM dynamics may contribute to the pathogenesis and/or post-acute sequelae of SARS-CoV-2 infection.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":299131,"datarank":0.41193085987531747,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.1705151730102024,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.1705151730102024,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":4,"citers_with_citation_signal":4,"citers_with_endowment":4,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"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":988582,"name":"Xuan Sabrina Pan","orcid":"0000-0003-3666-8793","position":1,"is_corresponding":false},{"id":326990,"name":"Denise C. Hocking","orcid":"0000-0003-2337-0357","position":2,"is_corresponding":false},{"id":513152,"name":"Emma G. Norris","orcid":"0000-0002-3717-9652","position":0,"is_corresponding":true}],"reference_count":108,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:31:40.528568Z","pmid":"35441172","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":[]}