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Structural Basis for the Function of the C-Terminal Proton Release Pathway in the Calcium Pump
The calcium pump (sarco/endoplasmic reticulum Ca(2+)-ATPase, SERCA) plays a major role in calcium homeostasis in muscle cells by clearing cytosolic Ca(2+) during muscle relaxation. Active Ca(2+) transport by SERCA involves the structural transition from a low-Ca(2+) affinity E2 state toward a high-C...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037123/ https://www.ncbi.nlm.nih.gov/pubmed/33805255 http://dx.doi.org/10.3390/ijms22073507 |
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author | Espinoza-Fonseca, L. Michel |
author_facet | Espinoza-Fonseca, L. Michel |
author_sort | Espinoza-Fonseca, L. Michel |
collection | PubMed |
description | The calcium pump (sarco/endoplasmic reticulum Ca(2+)-ATPase, SERCA) plays a major role in calcium homeostasis in muscle cells by clearing cytosolic Ca(2+) during muscle relaxation. Active Ca(2+) transport by SERCA involves the structural transition from a low-Ca(2+) affinity E2 state toward a high-Ca(2+) affinity E1 state of the pump. This structural transition is accompanied by the countertransport of protons to stabilize the negative charge and maintain the structural integrity of the transport sites and partially compensate for the positive charges of the two Ca(2+) ions passing through the membrane. X-ray crystallography studies have suggested that a hydrated pore located at the C-terminal domain of SERCA serves as a conduit for proton countertransport, but the existence and function of this pathway have not yet been fully characterized. We used atomistic simulations to demonstrate that in the protonated E2 state and the absence of initially bound water molecules, the C-terminal pore becomes hydrated in the nanosecond timescale. Hydration of the C-terminal pore is accompanied by the formation of water wires that connect the transport sites with the cytosol. Water wires are known as ubiquitous proton-transport devices in biological systems, thus supporting the notion that the C-terminal domain serves as a conduit for proton release. Additional simulations showed that the release of a single proton from the transport sites induces bending of transmembrane helix M5 and the interaction between residues Arg762 and Ser915. These structural changes create a physical barrier against full hydration of the pore and prevent the formation of hydrogen-bonded water wires once proton transport has occurred through this pore. Together, these findings support the notion that the C-terminal proton release pathway is a functional element of SERCA and also provide a mechanistic model for its operation in the catalytic cycle of the pump. |
format | Online Article Text |
id | pubmed-8037123 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-80371232021-04-12 Structural Basis for the Function of the C-Terminal Proton Release Pathway in the Calcium Pump Espinoza-Fonseca, L. Michel Int J Mol Sci Article The calcium pump (sarco/endoplasmic reticulum Ca(2+)-ATPase, SERCA) plays a major role in calcium homeostasis in muscle cells by clearing cytosolic Ca(2+) during muscle relaxation. Active Ca(2+) transport by SERCA involves the structural transition from a low-Ca(2+) affinity E2 state toward a high-Ca(2+) affinity E1 state of the pump. This structural transition is accompanied by the countertransport of protons to stabilize the negative charge and maintain the structural integrity of the transport sites and partially compensate for the positive charges of the two Ca(2+) ions passing through the membrane. X-ray crystallography studies have suggested that a hydrated pore located at the C-terminal domain of SERCA serves as a conduit for proton countertransport, but the existence and function of this pathway have not yet been fully characterized. We used atomistic simulations to demonstrate that in the protonated E2 state and the absence of initially bound water molecules, the C-terminal pore becomes hydrated in the nanosecond timescale. Hydration of the C-terminal pore is accompanied by the formation of water wires that connect the transport sites with the cytosol. Water wires are known as ubiquitous proton-transport devices in biological systems, thus supporting the notion that the C-terminal domain serves as a conduit for proton release. Additional simulations showed that the release of a single proton from the transport sites induces bending of transmembrane helix M5 and the interaction between residues Arg762 and Ser915. These structural changes create a physical barrier against full hydration of the pore and prevent the formation of hydrogen-bonded water wires once proton transport has occurred through this pore. Together, these findings support the notion that the C-terminal proton release pathway is a functional element of SERCA and also provide a mechanistic model for its operation in the catalytic cycle of the pump. MDPI 2021-03-29 /pmc/articles/PMC8037123/ /pubmed/33805255 http://dx.doi.org/10.3390/ijms22073507 Text en © 2021 by the author. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ). |
spellingShingle | Article Espinoza-Fonseca, L. Michel Structural Basis for the Function of the C-Terminal Proton Release Pathway in the Calcium Pump |
title | Structural Basis for the Function of the C-Terminal Proton Release Pathway in the Calcium Pump |
title_full | Structural Basis for the Function of the C-Terminal Proton Release Pathway in the Calcium Pump |
title_fullStr | Structural Basis for the Function of the C-Terminal Proton Release Pathway in the Calcium Pump |
title_full_unstemmed | Structural Basis for the Function of the C-Terminal Proton Release Pathway in the Calcium Pump |
title_short | Structural Basis for the Function of the C-Terminal Proton Release Pathway in the Calcium Pump |
title_sort | structural basis for the function of the c-terminal proton release pathway in the calcium pump |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037123/ https://www.ncbi.nlm.nih.gov/pubmed/33805255 http://dx.doi.org/10.3390/ijms22073507 |
work_keys_str_mv | AT espinozafonsecalmichel structuralbasisforthefunctionofthecterminalprotonreleasepathwayinthecalciumpump |