Monomeric <scp>α‐synuclein</scp> activates the plasma membrane calcium pump-Reference-Cited by-同舟云学术

Monomeric α‐synuclein activates the plasma membrane calcium pump

Published:2023-11-02 Issue:23 Volume:42 Page:
ISSN:0261-4189
Container-title:The EMBO Journal
language:en
Short-container-title:The EMBO Journal

Author:

Kowalski Antoni¹²³⁴^ORCID,Betzer Cristine²⁵,Larsen Sigrid Thirup¹²^ORCID,Gregersen Emil²⁵^ORCID,Newcombe Estella A³^ORCID,Bermejo Montaña Caballero¹²⁶^ORCID,Bendtsen Viktor Wisniewski¹²^ORCID,Diemer Jorin⁷^ORCID,Ernstsen Christina V⁸,Jain Shweta⁹^ORCID,Bou Alicia Espiña¹²,Langkilde Annette Eva¹⁰^ORCID,Nejsum Lene N⁸^ORCID,Klipp Edda⁷^ORCID,Edwards Robert⁹^ORCID,Kragelund Birthe B³^ORCID,Jensen Poul Henning²⁵^ORCID,Nissen Poul¹²^ORCID

Affiliation:

1. Department of Molecular Biology and Genetics Aarhus University Aarhus Denmark

2. Danish Research Institute of Translational Neuroscience – DANDRITE Aarhus University Aarhus Denmark

3. REPIN and Structural Biology and NMR Laboratory, Department of Biology University of Copenhagen Copenhagen Denmark

4. Department of Molecular Neurochemistry Medical University of Lodz Lodz Poland

5. Department of Biomedicine Aarhus University Aarhus Denmark

6. Department Biochemistry and Molecular Biology and Genetics, IBMP University of Extremadura Badajoz Spain

7. Theoretical Biophysics Humboldt‐Universität zu Berlin Berlin Germany

8. Department of Clinical Medicine Aarhus University Aarhus N Denmark

9. Departments of Neurology and Physiology University of California San Francisco San Francisco CA USA

10. Department of Drug Design and Pharmacology University of Copenhagen Copenhagen Denmark

Abstract

AbstractAlpha‐synuclein (aSN) is a membrane‐associated and intrinsically disordered protein, well known for pathological aggregation in neurodegeneration. However, the physiological function of aSN is disputed. Pull‐down experiments have pointed to plasma membrane Ca2+‐ATPase (PMCA) as a potential interaction partner. From proximity ligation assays, we find that aSN and PMCA colocalize at neuronal synapses, and we show that calcium expulsion is activated by aSN and PMCA. We further show that soluble, monomeric aSN activates PMCA at par with calmodulin, but independent of the autoinhibitory domain of PMCA, and highly dependent on acidic phospholipids and membrane‐anchoring properties of aSN. On PMCA, the key site is mapped to the acidic lipid‐binding site, located within a disordered PMCA‐specific loop connecting the cytosolic A domain and transmembrane segment 3. Our studies point toward a novel physiological role of monomeric aSN as a stimulator of calcium clearance in neurons through activation of PMCA.

Funder

H. Lundbeck A/S

Lundbeckfonden

Publisher

Springer Science and Business Media LLC

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Molecular Biology,General Neuroscience

Link

https://www.embopress.org/doi/pdf/10.15252/embj.2022111122

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