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FASEB J. 2018 Sep 19:fj201701413RRR. doi: 10.1096/fj.201701413RRR. [Epub ahead of print]

Calmodulin regulates MGRN1-GP78 interaction mediated ubiquitin proteasomal degradation system.

Author information

1
Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India.
2
Buchmann Institute for Molecular Life Sciences, Frankfurt Am Main, Germany.
3
Structural Biology and Bioinformatics Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIB-IICB), Kolkata, India.
4
Chemical Sciences Division, Saha Institute of Nuclear Physics, Kolkata, India.
5
Homi Bhabha National Institute, Mumbai, India.

Abstract

The mechanism by which the endoplasmic reticulum (ER) ubiquitin ligases sense stress to potentiate their activity is poorly understood. GP78, an ER E3 ligase, is best known for its role in ER-associated protein degradation, although its activity is also linked to mitophagy, ER-mitochondria junctions, and MAPK signaling, thus highlighting the importance of understanding its regulation. In healthy cells, Mahogunin really interesting new gene (RING) finger 1 (MGRN1) interacts with GP78 and proteasomally degrades it to alleviate mitophagy. Here, we identify calmodulin (CaM) as the adapter protein that senses fluctuating cytosolic Ca2+ levels and modulates the Ca2+-dependent MGRN1-GP78 interactions. When stress elevates cytosolic Ca2+ levels in cultured and primary neuronal cells, CaM binds to both E3 ligases and inhibits their interaction. Molecular docking, simulation, and biophysical studies show that CaM interacts with both proteins with different affinities and binding modes. The physiological impact of this interaction switch manifests in the regulation of ER-associated protein degradation, ER-mitochondria junctions, and relative distribution of smooth ER and rough ER.-Mukherjee, R., Bhattacharya, A., Sau, A., Basu, S., Chakrabarti, S., Chakrabarti, O. Calmodulin regulates MGRN1-GP78 interaction mediated ubiquitin proteasomal degradation system.

KEYWORDS:

apo CaM; calcium; holo CaM; proteasome; ubiquitin E3 ligase

PMID:
30230921
DOI:
10.1096/fj.201701413RRR

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