{"doi":"10.1242/dev.199988","title":"C2CD6 regulates targeting and organization of the CatSper calcium channel complex in sperm flagella","abstract":"The CatSper cation channel is essential for sperm capacitation and male fertility. The multi-subunit CatSper complexes form highly organized calcium signaling nanodomains on flagellar membranes. Here, we report identification of an uncharacterized protein, C2CD6, as a subunit of the mouse CatSper complex. C2CD6 contains a calcium-dependent, membrane-targeting C2 domain. C2CD6 associates with the CatSper calcium-selective, core-forming subunits. Deficiency of C2CD6 depletes the CatSper nanodomains from the flagellum and results in male sterility. C2CD6-deficient sperm are defective in hyperactivation and fail to fertilize oocytes both in vitro and in vivo. CatSper currents are present but at a significantly lower level in C2CD6-deficient sperm. Transient treatments with either Ca2+ ionophore, starvation, or a combination of both restore the fertilization capacity of C2CD6-deficient sperm. C2CD6 interacts with EFCAB9, a pH-dependent calcium sensor in the CatSper complex. We postulate that C2CD6 facilitates incorporation of the CatSper complex into the flagellar plasma membrane and may function as a calcium sensor. The identification of C2CD6 may enable the long-sought reconstitution of the CatSper ion channel complex in a heterologous system for male contraceptive development.","journal":"Development","year":2021,"id":169677,"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":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.947,"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":302813,"name":"Marıá Gracia Gervasi","orcid":"0000-0002-5468-2700","position":1,"is_corresponding":false},{"id":584031,"name":"Gerardo Orta","orcid":null,"position":2,"is_corresponding":false},{"id":302815,"name":"Darya A. Tourzani","orcid":"0000-0001-8451-2617","position":3,"is_corresponding":false},{"id":583592,"name":"José Luis de la Vega‐Beltrán","orcid":"0000-0003-0798-9408","position":4,"is_corresponding":false},{"id":301515,"name":"Gordon Ruthel","orcid":"0000-0001-9193-5589","position":5,"is_corresponding":false},{"id":583595,"name":"Alberto Darszon","orcid":"0000-0002-2502-0505","position":6,"is_corresponding":false},{"id":456906,"name":"Pablo E. Visconti","orcid":"0000-0001-9320-7518","position":7,"is_corresponding":false},{"id":316417,"name":"P. Jeremy Wang","orcid":"0000-0003-2311-4089","position":8,"is_corresponding":false},{"id":551669,"name":"Yang Fang","orcid":"0000-0002-8783-8652","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-18T23:46:15.560174Z","pmid":"34919125","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":[]}