| Structural highlights
6eey is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Gene: | SCRIB, CRIB1, KIAA0147, LAP4, SCRB1, VARTUL (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[SCRIB_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.
Function
[SCRIB_HUMAN] Scaffold protein involved in different aspects of polarized cells differentiation regulating epithelial and neuronal morphogenesis. Most probably functions in the establishment of apico-basal cell polarity. May function in cell proliferation regulating progression from G1 to S phase and as a positive regulator of apoptosis for instance during acinar morphogenesis of the mammary epithelium. May also function in cell migration and adhesion and hence regulate cell invasion through MAPK signaling. May play a role in exocytosis and in the targeting synaptic vesicles to synapses. Functions as an activator of Rac GTPase activity.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
Many G protein-coupled receptors (GPCRs) are organized as dynamic macromolecular complexes in human cells. Unraveling the structural determinants of unique GPCR complexes may identify unique protein:protein interfaces to be exploited for drug development. We previously reported alpha1D-adrenergic receptors (alpha1D-ARs) - key regulators of cardiovascular and central nervous system function - form homodimeric, modular PDZ protein complexes with cell-type specificity. Towards mapping alpha1D-AR complex architecture, biolayer interferometry (BLI) revealed the alpha1D-AR C-terminal PDZ ligand selectively binds the PDZ protein scribble (SCRIB) with >8x higher affinity than known interactors syntrophin, CASK and DLG1. Complementary in situ and in vitro assays revealed SCRIB PDZ domains 1 and 4 to be high affinity alpha1D-AR PDZ ligand interaction sites. SNAP-GST pull-down assays demonstrate SCRIB binds multiple alpha1D-AR PDZ ligands via a co-operative mechanism. Structure-function analyses pinpoint R1110(PDZ4) as a unique, critical residue dictating SCRIB:alpha1D-AR binding specificity. The crystal structure of SCRIB PDZ4 R1110G predicts spatial shifts in the SCRIB PDZ4 carboxylate binding loop dictate alpha1D-AR binding specificity. Thus, the findings herein identify SCRIB PDZ domains 1 and 4 as high affinity alpha1D-AR interaction sites, and potential drug targets to treat diseases associated with aberrant alpha1D-AR signaling.
Scribble co-operatively binds multiple alpha1D-adrenergic receptor C-terminal PDZ ligands.,Janezic EM, Harris DA, Dinh D, Lee KS, Stewart A, Hinds TR, Hsu PL, Zheng N, Hague C Sci Rep. 2019 Oct 1;9(1):14073. doi: 10.1038/s41598-019-50671-6. PMID:31575922[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Audebert S, Navarro C, Nourry C, Chasserot-Golaz S, Lecine P, Bellaiche Y, Dupont JL, Premont RT, Sempere C, Strub JM, Van Dorsselaer A, Vitale N, Borg JP. Mammalian Scribble forms a tight complex with the betaPIX exchange factor. Curr Biol. 2004 Jun 8;14(11):987-95. PMID:15182672 doi:10.1016/j.cub.2004.05.051
- ↑ Lahuna O, Quellari M, Achard C, Nola S, Meduri G, Navarro C, Vitale N, Borg JP, Misrahi M. Thyrotropin receptor trafficking relies on the hScrib-betaPIX-GIT1-ARF6 pathway. EMBO J. 2005 Apr 6;24(7):1364-74. Epub 2005 Mar 17. PMID:15775968 doi:10.1038/sj.emboj.7600616
- ↑ Qin Y, Capaldo C, Gumbiner BM, Macara IG. The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin. J Cell Biol. 2005 Dec 19;171(6):1061-71. Epub 2005 Dec 12. PMID:16344308 doi:10.1083/jcb.200506094
- ↑ Nagasaka K, Nakagawa S, Yano T, Takizawa S, Matsumoto Y, Tsuruga T, Nakagawa K, Minaguchi T, Oda K, Hiraike-Wada O, Ooishi H, Yasugi T, Taketani Y. Human homolog of Drosophila tumor suppressor Scribble negatively regulates cell-cycle progression from G1 to S phase by localizing at the basolateral membrane in epithelial cells. Cancer Sci. 2006 Nov;97(11):1217-25. Epub 2006 Sep 5. PMID:16965391 doi:10.1111/j.1349-7006.2006.00315.x
- ↑ Dow LE, Elsum IA, King CL, Kinross KM, Richardson HE, Humbert PO. Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling. Oncogene. 2008 Oct 9;27(46):5988-6001. doi: 10.1038/onc.2008.219. Epub 2008 Jul, 21. PMID:18641685 doi:10.1038/onc.2008.219
- ↑ Nola S, Sebbagh M, Marchetto S, Osmani N, Nourry C, Audebert S, Navarro C, Rachel R, Montcouquiol M, Sans N, Etienne-Manneville S, Borg JP, Santoni MJ. Scrib regulates PAK activity during the cell migration process. Hum Mol Genet. 2008 Nov 15;17(22):3552-65. doi: 10.1093/hmg/ddn248. Epub 2008 Aug, 20. PMID:18716323 doi:10.1093/hmg/ddn248
- ↑ Zhan L, Rosenberg A, Bergami KC, Yu M, Xuan Z, Jaffe AB, Allred C, Muthuswamy SK. Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma. Cell. 2008 Nov 28;135(5):865-78. doi: 10.1016/j.cell.2008.09.045. PMID:19041750 doi:10.1016/j.cell.2008.09.045
- ↑ Janezic EM, Harris DA, Dinh D, Lee KS, Stewart A, Hinds TR, Hsu PL, Zheng N, Hague C. Scribble co-operatively binds multiple alpha1D-adrenergic receptor C-terminal PDZ ligands. Sci Rep. 2019 Oct 1;9(1):14073. doi: 10.1038/s41598-019-50671-6. PMID:31575922 doi:https://dx.doi.org/10.1038/s41598-019-50671-6
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