Monomeric α-synuclein activates the plasma membrane calcium pump

被引：3

作者：

Kowalski, Antoni ^{[1
,2
,3
,4
,5
,13
]}

Betzer, Cristine ^{[2
,6
,14
]}

Larsen, Sigrid Thirup ^{[1
,2
]}

Gregersen, Emil ^{[2
,6
,15
]}

Newcombe, Estella A. ^{[3
,4
]}

Bermejo, Montana Caballero ^{[1
,2
,7
]}

Bendtsen, Viktor Wisniewski ^{[1
,2
]}

Diemer, Jorin ^{[8
]}

Ernstsen, Christina, V ^{[9
]}

Jain, Shweta ^{[10
,11
]}

Bou, Alicia Espina ^{[1
,2
]}

Langkilde, Annette Eva ^{[12
]}

Nejsum, Lene N. ^{[9
]}

Klipp, Edda ^{[8
]}

Edwards, Robert ^{[10
,11
]}

Kragelund, Birthe B. ^{[3
,4
]}

Jensen, Poul Henning ^{[2
,6
]}

Nissen, Poul ^{[1
,2
]}

机构：

[1] Aarhus Univ, Dept Mol Biol & Genet, Aarhus, Denmark

[2] Aarhus Univ, Danish Res Inst Translat Neurosci DANDRITE, Aarhus, Denmark

[3] Univ Copenhagen, Dept Biol, REPIN, Copenhagen, Denmark

[4] Univ Copenhagen, Dept Biol, Struct Biol & NMR Lab, Copenhagen, Denmark

[5] Med Univ Lodz, Dept Mol Neurochem, Lodz, Poland

[6] Aarhus Univ, Dept Biomed, Aarhus, Denmark

[7] Univ Extremadura, IBMP, Dept Biochem & Mol Biol & Genet, Badajoz, Spain

[8] Humboldt Univ, Theoret Biophys, Berlin, Germany

[9] Aarhus Univ, Dept Clin Med, Aarhus, Denmark

[10] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA

[11] Univ Calif San Francisco, Dept Physiol, San Francisco, CA USA

[12] Univ Copenhagen, Dept Drug Design & Pharmacol, Copenhagen, Denmark

[13] ImmunAware ApS, Horsholm, Denmark

[14] Regionshospitalet Godstrup, Reg Midtjylland, Herning, Denmark

[15] Aarhus Univ, Dept Clin Med, Aarhus, Denmark

来源：

EMBO JOURNAL | 2023年 / 42卷 / 23期

关键词：

alpha-synuclein; calcium; calmodulin; plasma membrane Ca2+-ATPase; presynapse; LIPID-BINDING REGION; RED-BLOOD-CELLS; PARKINSONS-DISEASE; CA2+ PUMP; PHOSPHOLIPID-BINDING; CALMODULIN-BINDING; IN-VIVO; LOCALIZATION; INHIBITION; EXPRESSION;

D O I：

10.15252/embj.2022111122

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Alpha-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.

引用

页数：21

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