6y2h | pdb_00006y2h
The crystal structure of human chloride intracellular channel protein 5
Structural highlights
Disease[CLIC5_HUMAN] Autosomal recessive non-syndromic sensorineural deafness type DFNB. The disease is caused by mutations affecting the gene represented in this entry. Function[CLIC5_HUMAN] Required for normal hearing (PubMed:24781754). It is necessary for the formation of stereocilia in the inner ear and normal development of the organ of Corti (By similarity). Can insert into membranes and form poorly selective ion channels that may also transport chloride ions. May play a role in the regulation of transepithelial ion absorption and secretion. Is required for the development and/or maintenance of the proper glomerular endothelial cell and podocyte architecture (PubMed:15184393, PubMed:18028448, PubMed:20335315). Plays a role in formation of the lens suture in the eye, which is important for normal optical properties of the lens (By similarity).[UniProtKB:Q8BXK9][1] [2] [3] [4] Publication Abstract from PubMedThe human chloride intracellular channel (hCLIC) family is thought to transition between globular and membrane-associated forms by exposure of a hydrophobic surface. However, the molecular identity of this surface, and the triggering events leading to its exposure, remain elusive. Here, by combining biochemical and structural approaches, together with mass spectrometry (MS) analyses, we show that hCLIC5 is inherently flexible. X-ray crystallography revealed the existence of a globular conformation, while small-angle X-ray scattering showed additional elongated forms consisting of exposure of the conserved hydrophobic inter-domain interface to the bulk phase. Tryptophan fluorescence measurements demonstrated that the transition to the membrane-associated form is enhanced by the presence of oxidative environment and lipids. Using MS, we identified a dose-dependent oxidation of a highly conserved cysteine residue, known to play a key role in the structurally related omega-class of glutathione-S-transferases. Hydrogen/deuterium exchange MS analysis revealed that oxidation of this cysteine facilitates the exposure of the conserved hydrophobic inter-domain interface. Together, our results pinpoint an oxidation of a specific cysteine residue as a triggering mechanism initializing the molecular commitment for membrane interaction in the CLIC family. Conserved cysteine dioxidation enhances membrane interaction of human Cl(-) intracellular channel 5.,Ferofontov A, Vankova P, Man P, Giladi M, Haitin Y FASEB J. 2020 Jun 17. doi: 10.1096/fj.202000399R. PMID:32725932[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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