5vwk | pdb_00005vwk
Crystal structure of human Scribble PDZ1:Beta-PIX complex
Structural highlights
DiseaseSCRIB_HUMAN The disease is caused by mutations affecting the gene represented in this entry. FunctionSCRIB_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 PubMedScribble 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
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