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Figures
- Fig. 1.
The mammalian CLIC family and structural relationship with omega-class GST (GSTO-1). (A) Phylogenetic analysis of the mammalian CLIC proteins based on sequence homology. The branch length is proportional to the number of substitutions per site. CLIC proteins are 236–253 aa in length. CLIC5 exists as isoform A and B, with CLIC5B (410 aa) having an extended N-terminal region. CLIC6 is atypical in that it is much larger (704 aa), and has a unique extended N-terminal region without sequence similarity to other proteins. (B) CLIC domain structure. The N-terminal thioredoxin-like and C-terminal α-helical domains of human CLIC4 are shown in light and dark blue, respectively. The thioredoxin-like domain has a hypothetical transmembrane region (light gray), the α-helical domain has a nuclear localization signal (dark gray). The red asterisk indicates the reactive Cys residue (Cys35 in CLIC4). The horizontal bar indicates the number of amino acids. (C) Tertiary structure of GSTO1 (left) and CLIC4 (right). Glutathione (GSH) is depicted in gray. The indicated residues in CLIC4 are essential for agonist-induced, RhoA-dependent translocation to the plasma membrane. See Littler et al. (2005, 2010) and Ponsioen et al. (2009) for further details. Molecular models were created by using the CCP4MG software (Potterton et al., 2004) with optimized models for the structures PDB:1EEM for GSTO1 and PDB:2AHE for CLIC4 downloaded from PDB_REDO (Joosten et al., 2012).
- Fig. 2.
Intracellular activities of CLIC proteins. (A) Overview of the cellular roles of CLIC1 to CLIC4. (1) Amyloid β (Aβ) peptide induces CLIC1 translocation and insertion into the plasma membrane, which is associated with NADPH oxidase-mediated oxygen species (ROS) production (Milton et al., 2008). (2) CLIC1 is detected on phagosomal membranes in macrophages undergoing phagocytosis and colocalizes with ERM proteins, RhoA and Rac2 (Jiang et al., 2012). (3, 4) CLIC2 and CLIC4 undergo rapid translocation to the plasma membrane upon GPCR stimulation (Lecat et al., 2015). (4) Upon stimulation with LPA, CLIC4 colocalizes with NHERF2 and β1 integrin at the plasma membrane and in a subset of Rab35-positive recycling endosome (Argenzio et al., 2014; Ponsioen et al., 2009). CLIC4 contributes to the internalization of β1 integrin (5) and its LPA-induced recycling back to the plasma membrane (Argenzio et al., 2014) (6). (7) CLIC4 stimulates retromer-mediated endosome trafficking in an actin- and Rab11-dependent manner (Chou et al., 2016). (8) CLIC3 colocalizes with LAMP1 in late endosomes from where it controls the recycling of α5β1 integrins in a Rab25-dependent manner (Dozynkiewicz et al., 2012). CLIC3 also regulates the recycling of matrix metallopeptidase 14 (MT1-MMP) in a Rab25-independent fashion (Macpherson et al., 2014). (9) TGFβ induces translocation of CLIC4 into the nucleus were it prevents the dephosphorylation of SMAD proteins to enhance transcription (Shukla et al., 2009). INFγ and LPS promote CLIC4 S-nitrosylation (N) and nuclear translocation (Malik et al., 2012). TGFβR, transforming growth factor β receptor, IFNR, interferon receptor; GPCR, G-protein-coupled receptor. (B) Activity of CLIC5. (1) CLIC5 colocalizes with ERM proteins in microvilli of polarized cells (Berryman and Goldenring, 2003). (2) CLIC5 recruits PIP kinases (PIPKs) to influence local phosphoinositide levels at the plasma membrane (Al-Momany et al., 2014). (3) CLIC5 stabilizes membrane-actin linkages at hair cell stereocilia in complex with ERM proteins and taperin (T) (Salles et al., 2014). See text for further details. E, ezrin; R, radixin; M, moesin.
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