Genome-wide kinase-MAM interactome screening reveals the role of CK2A1 in MAM Ca <sup>2+</sup> dynamics linked to DEE66-Reference-Cited by-同舟云学术

Genome-wide kinase-MAM interactome screening reveals the role of CK2A1 in MAM Ca ²⁺ dynamics linked to DEE66

Published:2023-07-31 Issue:32 Volume:120 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Thi My Nhung Truong¹^ORCID,Phuoc Long Nguyen²^ORCID,Diem Nghi Tran¹,Suh Yeongjun¹^ORCID,Hoang Anh Nguyen³,Jung Cheol Woon³^ORCID,Minh Triet Hong¹,Jung Minkyo⁴^ORCID,Woo Youngsik¹^ORCID,Yoo Jinyeong¹^ORCID,Noh Sujin¹^ORCID,Kim Soo Jeong¹^ORCID,Lee Su Been¹^ORCID,Park Seongoh⁵,Thomas Gary⁶,Simmen Thomas⁷^ORCID,Mun Jiyoung⁴,Rhee Hyun-Woo⁸^ORCID,Kwon Sung Won³^ORCID,Park Sang Ki¹

Affiliation:

1. Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea

2. Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 47392, Republic of Korea

3. College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea

4. Neural Circuit Research Group, Korea Brain Research Institute, Daegu 41062, Republic of Korea

5. School of Mathematics, Statistics and Data Science, Sungshin Women’s University, Seoul 02844, Republic of Korea

6. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA 15219

7. Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada

8. Department of Chemistry, Seoul National University, Seoul 08826, Korea

Abstract

The endoplasmic reticulum (ER) and mitochondria form a unique subcellular compartment called mitochondria-associated ER membranes (MAMs). Disruption of MAMs impairs Ca 2+ homeostasis, triggering pleiotropic effects in the neuronal system. Genome-wide kinase-MAM interactome screening identifies casein kinase 2 alpha 1 (CK2A1) as a regulator of composition and Ca 2+ transport of MAMs. CK2A1-mediated phosphorylation of PACS2 at Ser207/208/213 facilitates MAM localization of the CK2A1–PACS2–PKD2 complex, regulating PKD2-dependent mitochondrial Ca 2+ influx. We further reveal that mutations of PACS2 (E209K and E211K) associated with developmental and epileptic encephalopathy-66 (DEE66) impair MAM integrity through the disturbance of PACS2 phosphorylation at Ser207/208/213. This, in turn, causes the reduction of mitochondrial Ca 2+ uptake and the dramatic increase of the cytosolic Ca 2+ level, thereby, inducing neurotransmitter release at the axon boutons of glutamatergic neurons. In conclusion, our findings suggest a molecular mechanism that MAM alterations induced by pathological PACS2 mutations modulate Ca 2+ -dependent neurotransmitter release.

Funder

Samsung Science and Technology Foundation

National Research Foundation of Korea

Korean Ministry of Science and ICT

Ministry of Science and ICT, South Korea

NIH

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2303402120

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