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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
A lys-trp cation-π interaction mediates the dimerization and function of the chloride intracellular channel protein 1 transmembrane domain
Biochemistry, Volume 53, No. 1, Year 2014
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Description
Chloride intracellular channel protein 1 (CLIC1) is a dual-state protein that can exist either as a soluble monomer or in an integral membrane form. The oligomerization of the transmembrane domain (TMD) remains speculative despite it being implicated in pore formation. The extent to which electrostatic and van der Waals interactions drive folding and association of the dimorphic TMD is unknown and is complicated by the requirement of interactions favorable in both aqueous and membrane environments. Here we report a putative Lys37-Trp35 cation-π interaction and show that it stabilizes the dimeric form of the CLIC1 TMD in membranes. A synthetic 30-mer peptide comprising a K37M TMD mutant was examined in 2,2,2-trifluoroethanol, sodium dodecyl sulfate micelles, and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine liposomes using far-ultraviolet (UV) circular dichroism, fluorescence, and UV absorbance spectroscopy. Our data suggest that Lys37 is not implicated in the folding, stability, or membrane insertion of the TMD peptide. However, removal of this residue impairs the formation of dimers and higher-order oligomers. This is accompanied by a 30-fold loss of chloride influx activity, suggesting that dimerization modulates the rate of chloride conductance. We propose that, within membranes, individual TMD helices associate via a Lys37-mediated cation-π interaction to form active dimers. The latter findings are also supported by results of modeling a putative TMD dimer conformation in which Lys37 and Trp35 form cation-π pairs at the dimer interface. Dimeric helix bundles may then associate to form fully active ion channels. Thus, within a membrane-like environment, aromatic interactions involving a polar lysine side chain provide a thermodynamic driving force for helix-helix association. © 2013 American Chemical Society.
Authors & Co-Authors
Peter, Bradley
South Africa, Johannesburg
University of the Witwatersrand
Polyansky, Anton A.
Austria, Vienna
Universität Wien
Russian Federation, Moscow
Shemyakin-ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences
Fanucchi, Sylvia
South Africa, Johannesburg
University of the Witwatersrand
Dirr, Heini W.
South Africa, Johannesburg
University of the Witwatersrand
Statistics
Citations: 24
Authors: 4
Affiliations: 3
Identifiers
Doi:
10.1021/bi401433f
e-ISSN:
15204995