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A Ca(V)2.1 N-terminal fragment relieves the dominant-negative inhibition by an Episodic ataxia 2 mutant

Dahimene, S; Page, KM; Nieto-Rostro, M; Pratt, WS; D'Arco, M; Dolphin, AC; (2016) A Ca(V)2.1 N-terminal fragment relieves the dominant-negative inhibition by an Episodic ataxia 2 mutant. Neurobiology of Disease , 93 pp. 243-256. 10.1016/j.nbd.2016.05.020. Green open access

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Abstract

Episodic ataxia 2 (EA2) is an autosomal dominant disorder caused by mutations in the gene CACNA1A that encodes the pore-forming CaV2.1 calcium channel subunit. The majority of EA2 mutations reported so far are nonsense or deletion/insertion mutations predicted to form truncated proteins. Heterologous expression of wild-type CaV2.1, together with truncated constructs that mimic EA2 mutants, significantly suppressed wild-type calcium channel function, indicating that the truncated protein produces a dominant-negative effect (Jouvenceau et al., 2001; Page et al., 2004). A similar finding has been shown for CaV2.2 (Raghib et al., 2001). We show here that a highly conserved sequence in the cytoplasmic N-terminus is involved in this process, for both CaV2.1 and CaV2.2 channels. Additionally, we were able to interfere with the suppressive effect of an EA2 construct by mutating key N-terminal residues within it. We postulate that the N-terminus of the truncated channel plays an essential part in its interaction with the full-length CaV2.1, which prevents the correct folding of the wild-type channel. In agreement with this, we were able to disrupt the interaction between EA2 and the full length channel by co-expressing a free N-terminal peptide.

Type: Article
Title: A Ca(V)2.1 N-terminal fragment relieves the dominant-negative inhibition by an Episodic ataxia 2 mutant
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.nbd.2016.05.020
Publisher version: http://dx.doi.org/10.1016/j.nbd.2016.05.020
Language: English
Additional information: © 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, Episodic ataxia-2, P/Q-type calcium channel, Dominant negative suppression, N-terminus, Misfolded protein, GATED CALCIUM-CHANNELS, CA2+ CHANNELS, FUNCTIONAL-PROPERTIES, TRUNCATED CONSTRUCTS, ABSENCE EPILEPSY, SUBUNIT, MICE, IDENTIFICATION, SUPPRESSION, MODULATION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/1499818
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