6eey | pdb_00006eey
Crystal structure of human Scribble PDZ4 R1110G Mutant
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 PubMedMany 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
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