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HGNC Approved Gene Symbol: GOPC
Cytogenetic location: 6q22.1 Genomic coordinates (GRCh38) : 6:117,560,269-117,602,511 (from NCBI)
PIST is a PDZ domain-containing Golgi protein. PDZ domains contain approximately 90 amino acids and bind the extreme C terminus of proteins in a sequence-specific manner.
Using a yeast 2-hybrid screen of a day-9 mouse embryo cDNA library with a TC10 (605857) gain-of-function mutant as bait, followed by EST database searching and RACE, Neudauer et al. (2001) obtained cDNAs encoding mouse and human PIST. The deduced 454-amino acid human protein, which is approximately 92% identical to the mouse protein, contains 2 putative coiled-coil domains, with a potential leucine zipper in the second domain, followed by a novel region conserved in mouse and worm, and a PDZ domain. Northern blot analysis revealed ubiquitous expression of a 4.4-kb transcript, with highest expression in brain and heart.
By EST database searching with a PDZ domain of rat Psd95 (602887) as the probe, followed by PCR and probing of a myeloid leukemia cDNA library, Charest et al. (2001) obtained a cDNA encoding FIG. In addition to the protein structures identified by Neudauer et al. (2001), the authors reported multiple phosphorylation sites in FIG. They found that the FIG PDZ domains cluster with those of the syntrophin family (e.g., SNTA1, 601017). Western blot analysis showed expression of a 59-kD protein in all mouse tissues examined. Immunofluorescence microscopy demonstrated that perinuclear, brefeldin A-sensitive Golgi localization occurs through the second, or C-terminal, coiled-coil domain (CCD) and is independent of the leucine zipper.
Independently, Yao et al. (2001) also cloned and characterized PIST, which they termed GOPC.
Binding and mutation analyses by Neudauer et al. (2001) indicated a leucine zipper-dependent interaction of PIST with GTP-bound TC10 and with PIST itself, but not with other Rho GTPases.
Binding analysis and immunofluorescence microscopy by Yao et al. (2001) indicated that the PDZ domain of GOPC interacts with the C-terminal domain of frizzled-5 (FZD5; 601723) or FZD8 (606146) in the Golgi apparatus before the FZD proteins translocate by the secretory pathway to the plasma membrane.
Western blot analysis and immunofluorescence microscopy by Charest et al. (2001) showed that FIG interacts through its C-terminal CCD with syntaxin-6 (STX6; 603944) in the Golgi apparatus. They proposed that FIG may be involved in membrane vesicle trafficking.
Coimmunoprecipitation analysis and immunofluorescence microscopy by Cheng et al. (2002) showed that PIST, which they called CAL, interacts with the C terminus of cystic fibrosis transmembrane conductance regulator (CFTR; 602421) in the Golgi. Functional analysis indicated that the CAL-CFTR interaction results in a reduction of the CFTR chloride current by a selective inhibition of cell surface CFTR expression; this could be reversed by competition from NHERF (604990).
Cheng et al. (2010) showed that STX6 was involved in CAL-mediated downregulation of CFTR. While CAL bound the C terminus of CFTR, STX6 independently bound the N terminus of CFTR. Overexpression of STX6 reduced cell surface expression of CFTR and caused its instability, but not in the absence of CAL and not in the presence of a lysosome inhibitor. STX6 and CAL had no effect on the stability of CFTR with the cystic fibrosis (219700)-associated delta-F508 mutation (602421.0001), which is retained in the ER and undergoes ER-associated degradation. Cheng et al. (2010) concluded that STX6 and CAL function in the trans-Golgi network and direct trafficking of CFTR to the lysosome.
Using yeast 2-hybrid system experiments, Yue et al. (2002) determined that an isoform of PIST in mice, which they called nPist, interacts with both Grid2 (602368) and Becn1 (604378). Coimmunoprecipitation and colocalization experiments demonstrated that the specific interaction of Grid2 and nPist requires the C terminus of Grid2 and the nPist PDZ domain. GST pull-down assays, coimmunoprecipitation assays, and colocalization experiments confirmed the interaction between nPist and Becn1. In transfected cells, nPist and Becn1 acted synergistically to induce autophagy. Yue et al. (2002) proposed that nPist, Grid2, and Becn1 form a complex in cerebellar Purkinje cells in vivo and suggested that disruption of this complex in Grid2 mutant lurcher mice results in activation of autophagy in lurcher Purkinje cells.
FIG/ROS Fusion Protein
Charest et al. (2003) reported the analysis of an interstitial deletion of 240 kb on 6q21 that fused the FIG gene to the receptor protein tyrosine kinase (RTK) ROS1 (165020) in glioblastoma cell lines. The resulting FIG/ROS fusion protein is a constitutively activated tyrosine kinase. This was the first example of a genomic event that leads to the formation of an RTK fusion protein in an astrocytoma.
The International Radiation Hybrid Mapping consortium mapped the PIST gene to chromosome 6 (WI-12920).
Yao et al. (2002) showed that GOPC is predominantly localized at the trans-Golgi region in round spermatids, and that male mice in which GOPC has been disrupted are infertile with globozoospermia (102530). The primary defect was the fragmentation of acrosomes in early round spermatids, and abnormal vesicles that failed to fuse to developing acrosomes were apparent. In later stages, nuclear malformation and an abnormal arrangement of mitochondria, which are also characteristic features of human globozoospermia, were observed. Intracytoplasmic sperm injection of such malformed sperm into oocytes resulted in cleavage into blastocysts only when injected oocytes were activated. The authors concluded that GOPC provides important clues to understanding the mechanisms underlying spermatogenesis, and the GOPC-deficient mouse may be a unique and valuable model for human globozoospermia.
Charest, A., Lane, K., McMahon, K., Housman, D. E. Association of a novel PDZ domain-containing peripheral Golgi protein with the Q-SNARE (Q-soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment protein receptor) protein syntaxin 6. J. Biol. Chem. 276: 29456-29465, 2001. [PubMed: 11384996] [Full Text: https://doi.org/10.1074/jbc.M104137200]
Charest, A., Lane, K., McMahon, K., Park, J., Preisinger, E., Conroy, H., Housman, D. Fusion of FIG to the receptor tyrosine kinase ROS in a glioblastoma with an interstitial del(6)(q21q21). Genes Chromosomes Cancer 37: 58-71, 2003. [PubMed: 12661006] [Full Text: https://doi.org/10.1002/gcc.10207]
Cheng, J., Cebotaru, V., Cebotaru, L., Guggino, W. B. Syntaxin 6 and CAL mediate the degradation of the cystic fibrosis transmembrane conductance regulator. Molec. Biol. Cell 21: 1178-1187, 2010. [PubMed: 20130090] [Full Text: https://doi.org/10.1091/mbc.e09-03-0229]
Cheng, J., Moyer, B. D., Milewski, M., Loffing, J., Ikeda, M., Mickle, J. E., Cutting, G. R., Li, M., Stanton, B. A., Guggino, W. B. A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression. J. Biol. Chem. 277: 3520-3529, 2002. [PubMed: 11707463] [Full Text: https://doi.org/10.1074/jbc.M110177200]
Neudauer, C. L., Joberty, G., Macara, I. G. PIST: a novel PDZ/coiled-coil domain binding partner for the Rho-family GTPase TC10. Biochem. Biophys. Res. Commun. 280: 541-547, 2001. [PubMed: 11162552] [Full Text: https://doi.org/10.1006/bbrc.2000.4160]
Yao, R., Ito, C., Natsume, Y., Sugitani, Y., Yamanaka, H., Kuretake, S., Yanagida, K., Sato, A., Toshimori, K., Noda, T. Lack of acrosome formation in mice lacking a Golgi protein, GOPC. Proc. Nat. Acad. Sci. 99: 11211-11216, 2002. [PubMed: 12149515] [Full Text: https://doi.org/10.1073/pnas.162027899]
Yao, R., Maeda, T., Takada, S., Noda, T. Identification of a PDZ domain containing Golgi protein, GOPC, as an interaction partner of frizzled. Biochem. Biophys. Res. Commun. 286: 771-778, 2001. [PubMed: 11520064] [Full Text: https://doi.org/10.1006/bbrc.2001.5430]
Yue, Z., Horton, A., Bravin, M., DeJager, P. L., Selimi, F., Heintz, N. A novel protein complex linking the delta-2 glutamate receptor and autophagy: implications for neurodegeneration in Lurcher mice. Neuron 35: 921-933, 2002. [PubMed: 12372286] [Full Text: https://doi.org/10.1016/s0896-6273(02)00861-9]