The SERCA residue Glu340 mediates interdomain communication that guides Ca 2+ transport.

Autor:	Geurts MMG; Department of Biochemistry, University of Oxford, OX1 3QU Oxford, United Kingdom., Clausen JD; Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.; Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark., Arnou B; Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.; Institute for Integrative Biology of the Cell (I2BC), Commissariat à l'Energie Atomique et aux Energies Alternatives, CNRS, Université Paris-Saclay, 91198 Gif-sur-Yvette, France., Montigny C; Institute for Integrative Biology of the Cell (I2BC), Commissariat à l'Energie Atomique et aux Energies Alternatives, CNRS, Université Paris-Saclay, 91198 Gif-sur-Yvette, France., Lenoir G; Institute for Integrative Biology of the Cell (I2BC), Commissariat à l'Energie Atomique et aux Energies Alternatives, CNRS, Université Paris-Saclay, 91198 Gif-sur-Yvette, France., Corey RA; Department of Biochemistry, University of Oxford, OX1 3QU Oxford, United Kingdom., Jaxel C; Institute for Integrative Biology of the Cell (I2BC), Commissariat à l'Energie Atomique et aux Energies Alternatives, CNRS, Université Paris-Saclay, 91198 Gif-sur-Yvette, France., Møller JV; Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark., Nissen P; Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.; Danish Research Institute of Translational Neuroscience-DANDRITE, Nordic European Molecular Biology Laboratory Partnership for Molecular Medicine, Aarhus University, 8000 Aarhus C, Denmark., Andersen JP; Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark., le Maire M; Institute for Integrative Biology of the Cell (I2BC), Commissariat à l'Energie Atomique et aux Energies Alternatives, CNRS, Université Paris-Saclay, 91198 Gif-sur-Yvette, France., Bublitz M; Department of Biochemistry, University of Oxford, OX1 3QU Oxford, United Kingdom; maike.bublitz@bioch.ox.ac.uk.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Dec 08; Vol. 117 (49), pp. 31114-31122. Date of Electronic Publication: 2020 Nov 23.
DOI:	10.1073/pnas.2014896117
Abstrakt:	The sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) is a P-type ATPase that transports Ca 2+ from the cytosol into the sarco(endo)plasmic reticulum (SR/ER) lumen, driven by ATP. This primary transport activity depends on tight coupling between movements of the transmembrane helices forming the two Ca 2+ -binding sites and the cytosolic headpiece mediating ATP hydrolysis. We have addressed the molecular basis for this intramolecular communication by analyzing the structure and functional properties of the SERCA mutant E340A. The mutated Glu340 residue is strictly conserved among the P-type ATPase family of membrane transporters and is located at a seemingly strategic position at the interface between the phosphorylation domain and the cytosolic ends of 5 of SERCA's 10 transmembrane helices. The mutant displays a marked slowing of the Ca 2+ -binding kinetics, and its crystal structure in the presence of Ca 2+ and ATP analog reveals a rotated headpiece, altered connectivity between the cytosolic domains, and an altered hydrogen bonding pattern around residue 340. Supported by molecular dynamics simulations, we conclude that the E340A mutation causes a stabilization of the Ca 2+ sites in a more occluded state, hence displaying slowed dynamics. This finding underpins a crucial role of Glu340 in interdomain communication between the headpiece and the Ca 2+ -binding transmembrane region. Competing Interests: The authors declare no competing interest. (Copyright © 2020 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu