Are Inositol Polyphosphates the Missing Link in Dynamic Cullin RING Ligase Regulation by the COP9 Signalosome?

Biomolecules
Xiaozhe Zhang, Feng Rao

Abstract

The E3 ligase activity of Cullin RING Ligases (CRLs) is controlled by cycles of neddylation/deneddylation and intimately regulated by the deneddylase COP9 Signalosome (CSN), one of the proteasome lid-CSN-initiation factor 3 (PCI) domain-containing "Zomes" complex. Besides catalyzing the removal of stimulatory Cullin neddylation, CSN also provides a docking platform for other proteins that might play a role in regulating CRLs, notably protein kinases and deubiquitinases. During the CRL activity cycle, CRL-CSN complexes are dynamically assembled and disassembled. Mechanisms underlying complex dynamics remain incompletely understood. Recently, the inositol polyphosphate metabolites (IP6, IP7) and their metabolic enzymes (IP5K, IP6K) have been discovered to participate in CRL-CSN complex formation as well as stimulus-dependent dissociation. Here we discuss these mechanistic insights in light of recent advances in elucidating structural basis of CRL-CSN complexes.

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Citations

Jan 3, 2020·Journal of Integrative Plant Biology·Nanxun QinXing Wang Deng
Mar 25, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sandip MukherjeeAnutosh Chakraborty
Feb 13, 2020·Proceedings of the National Academy of Sciences of the United States of America·Hong LinFeng Rao

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Methods Mentioned

BETA
neddylation
dynamic dissociation

Clinical Trials Mentioned

NCT03268954

Software Mentioned

Mass
Spec

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