4c7a
Crystal structure of the Smoothened CRD, selenomethionine-labeledCrystal structure of the Smoothened CRD, selenomethionine-labeled
Structural highlights
FunctionSMO_DANRE G protein-coupled receptor which associates with the patched protein (ptch) to transduce Hedgehog protein signaling. Binding of sonic hedgehog (shh) to its receptor patched prevents inhibition of smoothened (smo) by patched. When active, smo binds to and sequesters protein kinase A catalytic subunit prkaca at the cell membrane, preventing prkaca-mediated phosphorylation of gli transcription factors which releases the gli proteins from prkaca-mediated inhibition and allows for transcriptional activation of Hedgehog signaling pathway target genes (By similarity). Required for the development of primary and secondary motoneurons but not for the specification of midbrain dopaminergic neurons or development of the medial floor plate (PubMed:11493557). Required for induction of lateral floor plate and posterior motoneurons, anterior neural plate patterning, dorsoventral forebrain patterning, dorsoventral retinal patterning, optic stalk development, and formation of the forebrain primary axonal scaffold (PubMed:11566855). Required to regulate the formation of a subset of cerebellar neurons by limiting wnt1 expression which controls cerebellar expression of transcription factor olig2 (PubMed:18423594). Required for development of the pancreas (PubMed:34087472). Required for muscle development (PubMed:16136078). Required for the formation of a single continuous intestinal lumen from multiple discontinuous lumens, probably by regulating remodeling through rab11a-mediated trafficking to facilitate lumen fusion (PubMed:24504339). Required for development of the adenohypophysis (PubMed:11566855, PubMed:12606279). Required for anteroposterior patterning of the otic vesicle (PubMed:12588855). Required for development of the anterior craniofacial skeleton (PubMed:16481351). Required for patterning of the caudal fin (PubMed:17597528). Required during gastrulation and early somitogenesis stages to promote cardiomyocyte formation by regulating the specification of myocardial progenitors (PubMed:18842815). Required for induction of arterial endothelial cell formation by repressing venous cell fate (PubMed:20193674).[UniProtKB:P56726][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] Publication Abstract from PubMedThe Hedgehog (Hh) signal is transduced across the membrane by the heptahelical protein Smoothened (Smo), a developmental regulator, oncoprotein and drug target in oncology. We present the 2.3 A crystal structure of the extracellular cysteine rich domain (CRD) of vertebrate Smo and show that it binds to oxysterols, endogenous lipids that activate Hh signaling. The oxysterol-binding groove in the Smo CRD is analogous to that used by Frizzled 8 to bind to the palmitoleyl group of Wnt ligands and to similar pockets used by other Frizzled-like CRDs to bind hydrophobic ligands. The CRD is required for signaling in response to native Hh ligands, showing that it is an important regulatory module for Smo activation. Indeed, targeting of the Smo CRD by oxysterol-inspired small molecules can block signaling by all known classes of Hh activators and by clinically relevant Smo mutants. DOI:http://dx.doi.org/10.7554/eLife.01340.001. Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling.,Nachtergaele S, Whalen DM, Mydock LK, Zhao Z, Malinauskas T, Krishnan K, Ingham PW, Covey DF, Siebold C, Rohatgi R Elife. 2013 Oct 29;2:e01340. doi: 10.7554/eLife.01340. PMID:24171105[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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