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NBCe1\u2010B exhibits only basal activity due to the action of the auto\u2010inhibition domain (AID) in its unique amino\u2010terminus. However, NBCe1\u2010B can be activated by interaction with the IP3R\u2010binding protein released with inositol 1,4,5\u2010trisphosphate (IRBIT). Here, we investigate the molecular mechanism underlying the auto\u2010inhibition of NBCe1\u2010B and its activation by IRBIT. The IRBIT\u2010binding domain (IBD) of NBCe1\u2010B spans residues 1\u221252, essentially consisting of two arms, one negatively charged (residues 1\u221224) and the other positively charged (residues 40\u221252). The AID mainly spans residues 40\u221285, overlapping with the IBD in the positively charged arm. The magnitude of auto\u2010inhibition of NBCe1\u2010B is greatly decreased by manipulating the positively charged residues in the AID or by replacing a set of negatively charged residues with neutral ones in the transmembrane domain. The interaction between IRBIT and NBCe1\u2010B is abolished by mutating a set of negatively charged Asp\/Glu residues (to Asn\/Gln) plus a set of Ser\/Thr residues (to Ala) in the PEST domain of IRBIT. However, this interaction is not affected by replacing the same set of Ser\/Thr residues in the PEST domain with Asp. We propose that: (1) the AID, acting as a brake, binds to the transmembrane domain via electrostatic interaction to slow down NBCe1\u2010B; (2) IRBIT activates NBCe1\u2010B by releasing the brake from the transmembrane domain.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp280578","type":"journal-article","created":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T17:30:06Z","timestamp":1606325406000},"page":"1151-1172","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["IRBIT activates NBCe1\u2010B by releasing the auto\u2010inhibition module from the transmembrane domain"],"prefix":"10.1113","volume":"599","author":[{"given":"Pan","family":"Su","sequence":"first","affiliation":[{"name":"Key Laboratory of Molecular Biophysics of Ministry of Education School of Life Science &amp; Technology Huazhong University of Science &amp; Technology  Wuhan Hubei 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