Journal
FEBS JOURNAL
Volume 278, Issue 10, Pages 1662-1675Publisher
WILEY
DOI: 10.1111/j.1742-4658.2011.08086.x
Keywords
chloride intracellular channel protein; CLIC4; importin-alpha; nuclear localization signal (NLS); nucleocytoplasmic transport
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It has been reported that a human chloride intracellular channel (CLIC) protein, CLIC4, translocates to the nucleus in response to cellular stress, facilitated by a putative CLIC4 nuclear localization signal (NLS). The CLIC4 NLS adopts an a-helical structure in the native CLIC4 fold. It is proposed that CLIC4 is transported to the nucleus via the classical nuclear import pathway after binding the import receptor, importin-a. In this study, we have determined the X-ray crystal structure of a truncated form of importin-a lacking the importin-alpha binding domain, bound to a CLIC4 NLS peptide. The NLS peptide binds to the major binding site in an extended conformation similar to that observed for the classical simian virus 40 large T-antigen NLS. A Tyr residue within the CLIC4 NLS makes surprisingly favourable interactions by forming side-chain hydrogen bonds to the importin-a backbone. This structural evidence supports the hypothesis that CLIC4 translocation to the nucleus is governed by the importin-a nuclear import pathway, provided that CLIC4 can undergo a conformational rearrangement that exposes the NLS in an extended conformation.
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