Proton Countertransport and Coupled Gating in the Sarcoplasmic Reticulum Calcium Pump. Issue 24 (7th December 2018)

• Record Type: Journal Article
• Authors: Rui, Huan; Das, Avisek; Nakamoto, Robert; Roux, Benoît
• Is Part Of: Journal of molecular biology. Volume 430:Issue 24(2018)
• Page Start: 5050
• Page End: 5065
• Publication Date: 2018-12-07
• Subjects: SERCA -- ion pumps -- conformational transition -- molecular dynamics simulation -- string method; SERCA calcium pump of the sarcoplasmic reticulum -- TM transmembrane -- MD molecular dynamics; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2018.10.014
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: The calcium pump of the sarcoplasmic reticulum (SERCA) is an ATP-driven active transporter of Ca 2+ ions that functions via an "alternating-access" cycle mechanism. In each cycle, SERCA transports two Ca 2+ ions toward the lumen of the sarcoplasmic reticulum and two to three protons to the cytoplasm. How the latter conformational transition is coupled to cytoplasmic release of protons remains poorly understood. The present computational study shows how the mechanism of proton countertransport is coupled to the alternating access gating process in SERCA. Molecular dynamics simulation trajectories are generated starting from a series of configurations taken along the E2 to E1 transition pathway determined by the string method with swarms-of-trajectories. Simulations of different protonation configurations at the binding sites reveal how deprotonation events affect the opening of the cytoplasmic gate. The results show that there is a strong coupling between the chronological order of deprotonation, the entry of water molecules into the TM region, and the opening of the cytoplasmic gate. Deprotonation of E309 and E771 is sequential with E309 being the first to lose the proton. The deprotonation promotes the opening of the cytoplasmic gate but leads to a productive gating transition only if it occurs after the transmembrane domain has reached an intermediate conformation. Deprotonation of E309 and E771 is unproductive when it occurs too early because it causes the re-opening of the luminal gate. Graphical Abstract: Highlights: Molecular dynamics simulation show how the mechanism of proton countertransport is coupled to the E2 to E1 transition in the sarcoplasmic reticulum ATP-driven calcium pump SERCA. Strong coupling between the chronological order of deprotonation, the entry of water molecules into the transmembrane region, and the opening of the cytoplasmic gate Deprotonation of E309 and E771 is sequential with E309 being the first to lose the proton. Deprotonation of E309 and E771 promotes the opening of the cytoplasmic gate, but it is unproductive when it occurs too early because it causes the re-opening of the luminal gate.