| Structural highlights
5vwc 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.
| | Ligands: | EDO |
| Related: | 2w4f |
| 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
Scribble is a highly conserved protein regulator of cell polarity that has been demonstrated to function as a tumour suppressor or, conversely, as an oncogene in a context-dependent manner, and it also controls many physiological processes ranging from immunity to memory. Scribble consists of a leucine-rich repeat domain and four PDZ domains, with the latter being responsible for most of Scribbles complex formation with other proteins. Given the similarities of the Scribble PDZ domains sequences in their binding grooves, it is common for these domains to show overlapping preferences for the same ligand. Yet, Scribble PDZ domains can still exhibit unique binding profiles toward other ligands. This raises the fundamental question as to how these PDZ domains discriminate ligands and exert specificities in Scribble complex formation. To better understand how Scribble PDZ domains direct cell polarity signalling, we investigated here their interactions with the well characterised Scribble binding partner beta-PIX, a guanine nucleotide exchange factor. We report the interaction profiles of all isolated Scribble PDZ domains with a beta-PIX peptide. We show that Scribble PDZ1 and PDZ3 are the major interactors with beta-PIX, and reveal a distinct binding hierarchy in the interactions between the individual Scribble PDZ domains and beta-PIX. Furthermore, using crystal structures of PDZ1 and PDZ3 bound to beta-PIX we define the structural basis for Scribbles ability to specifically engage beta-PIX via its PDZ domains, and provide a mechanistic platform for understanding Scribble-beta-PIX coordinated cellular functions such as directional cell migration.
Structural basis for the differential interaction of Scribble PDZ domains with the guanine nucleotide exchange factor beta-PIX.,Lim KYB, Godde NJ, Humbert PO, Kvansakul M J Biol Chem. 2017 Oct 23. pii: jbc.M117.799452. doi: 10.1074/jbc.M117.799452. PMID:29061852[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
- ↑ Lim KYB, Godde NJ, Humbert PO, Kvansakul M. Structural basis for the differential interaction of Scribble PDZ domains with the guanine nucleotide exchange factor beta-PIX. J Biol Chem. 2017 Oct 23. pii: jbc.M117.799452. doi: 10.1074/jbc.M117.799452. PMID:29061852 doi:https://dx.doi.org/10.1074/jbc.M117.799452
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