Evaluation of the membrane-spanning domain of ClC-2

The Biochemical Journal
Mohabir RamjeesinghChristine E Bear

Abstract

The ClC family of chloride channels and transporters includes several members in which mutations have been associated with human disease. An understanding of the structure-function relationships of these proteins is essential for defining the molecular mechanisms underlying pathogenesis. To date, the X-ray crystal structures of prokaryotic ClC transporter proteins have been used to model the membrane domains of eukaryotic ClC channel-forming proteins. Clearly, the fidelity of these models must be evaluated empirically. In the present study, biochemical tools were used to define the membrane domain boundaries of the eukaryotic protein, ClC-2, a chloride channel mutated in cases of idiopathic epilepsy. The membrane domain boundaries of purified ClC-2 and accessible cysteine residues were determined after its functional reconstitution into proteoliposomes, labelling using a thiol reagent and proteolytic digestion. Subsequently, the lipid-embedded and soluble fragments generated by trypsin-mediated proteolysis were studied by MS and coverage of approx. 71% of the full-length protein was determined. Analysis of these results revealed that the membrane-delimited boundaries of the N- and C-termini of ClC-2 and the position of several ...Continue Reading

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Oct 16, 2009·Annual Review of Physiology·Charity DuranH Criss Hartzell
Sep 20, 2008·The Journal of Physiology·Jennie Garcia-OlivaresChristoph Fahlke
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Jan 30, 2015·Physiological Reports·Katherine R HenryPamela L Zeitlin

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