A Novel Degradation Signal Derived from Distal C-terminal Frameshift Mutations of KCNQ2 Protein Which Cause Neonatal Epilepsy

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2011 Sep 23

PMID 21937445

Citations 5

Authors

Jun Su

Xu Cao

KeWei Wang

Affiliations

Soon will be listed here.

Abstract

Benign familial neonatal convulsions is an autosomal-dominant idiopathic form of epilepsy primarily caused by gene mutations of the voltage-gated Kv7.2/KCNQ2/M-channel that exert only partial dominant-negative effects. However, the mechanism underlying the incomplete dominance of channel mutations, which cause epilepsy in infancy, remains unknown. Using mutagenesis and biochemistry combined with electrophysiology, we identified a novel degradation signal derived from distal C-terminal frameshift mutations, which impairs channel function. This degradation signal, transferable to non-channel CD4, can lead to accelerated degradation of mutant proteins through ubiquitin-independent proteasome machinery but does not affect mRNA quantity and protein trafficking. Functional dissection of this signal has revealed a key five-amino acid (RCXRG) motif critical for degradation. Taken together, our findings reveal a mechanism by which proteins that carry this signal are subject to degradation, leading to M-current dysfunction, which causes epilepsy.

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