Proteopedia

6esp

Proteome-wide analysis of phospho-regulated PDZ domain interactionsProteome-wide analysis of phospho-regulated PDZ domain interactions

Structural highlights

6esp is a 1 chain structure with sequence from Human. Full experimental 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

A key function of reversible protein phosphorylation is to regulate protein-protein interactions, many of which involve short linear motifs (3-12 amino acids). Motif-based interactions are difficult to capture because of their often low-to-moderate affinities. Here, we describe phosphomimetic proteomic peptide-phage display, a powerful method for simultaneously finding motif-based interaction and pinpointing phosphorylation switches. We computationally designed an oligonucleotide library encoding human C-terminal peptides containing known or predicted Ser/Thr phosphosites and phosphomimetic variants thereof. We incorporated these oligonucleotides into a phage library and screened the PDZ (PSD-95/Dlg/ZO-1) domains of Scribble and DLG1 for interactions potentially enabled or disabled by ligand phosphorylation. We identified known and novel binders and characterized selected interactions through microscale thermophoresis, isothermal titration calorimetry, and NMR We uncover site-specific phospho-regulation of PDZ domain interactions, provide a structural framework for how PDZ domains accomplish phosphopeptide binding, and discuss ligand phosphorylation as a switching mechanism of PDZ domain interactions. The approach is readily scalable and can be used to explore the potential phospho-regulation of motif-based interactions on a large scale.

Proteome-wide analysis of phospho-regulated PDZ domain interactions.,Sundell GN, Arnold R, Ali M, Naksukpaiboon P, Orts J, Guntert P, Chi CN, Ivarsson Y Mol Syst Biol. 2018 Aug 20;14(8):e8129. PMID:30126976[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ Sundell GN, Arnold R, Ali M, Naksukpaiboon P, Orts J, Guntert P, Chi CN, Ivarsson Y. Proteome-wide analysis of phospho-regulated PDZ domain interactions. Mol Syst Biol. 2018 Aug 20;14(8):e8129. PMID:30126976
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