6bd4
Crystal structure of human apo-Frizzled4 receptor
Structural highlights
DiseaseFZD4_HUMAN Retinopathy of prematurity;Familial exudative vitreoretinopathy;Persistent hyperplastic primary vitreous. The disease is caused by mutations affecting the gene represented in this entry. FunctionFZD4_HUMAN Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin (CTNNB1) canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin (CTNNB1) and activation of Wnt target genes. Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP). In retina, it can be both activated by Wnt protein-binding, but also by a Wnt-independent signaling via binding of norrin (NDP), promoting in both cases beta-catenin (CTNNB1) accumulation and stimulation of LEF/TCF-mediated transcriptional programs. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues.RUBR_CLOPA Rubredoxin is a small nonheme, iron protein lacking acid-labile sulfide. Its single Fe, chelated to 4 Cys, functions as an electron acceptor and may also stabilize the conformation of the molecule. Publication Abstract from PubMedFrizzled receptors (FZDs) are class-F G-protein-coupled receptors (GPCRs) that function in Wnt signalling and are essential for developing and adult organisms(1,2). As central mediators in this complex signalling pathway, FZDs serve as gatekeeping proteins both for drug intervention and for the development of probes in basic and in therapeutic research. Here we present an atomic-resolution structure of the human Frizzled 4 receptor (FZD4) transmembrane domain in the absence of a bound ligand. The structure reveals an unusual transmembrane architecture in which helix VI is short and tightly packed, and is distinct from all other GPCR structures reported so far. Within this unique transmembrane fold is an extremely narrow and highly hydrophilic pocket that is not amenable to the binding of traditional GPCR ligands. We show that such a pocket is conserved across all FZDs, which may explain the long-standing difficulties in the development of ligands for these receptors. Molecular dynamics simulations on the microsecond timescale and mutational analysis uncovered two coupled, dynamic kinks located at helix VII that are involved in FZD4 activation. The stability of the structure in its ligand-free form, an unfavourable pocket for ligand binding and the two unusual kinks on helix VII suggest that FZDs may have evolved a novel ligand-recognition and activation mechanism that is distinct from that of other GPCRs. Crystal structure of the Frizzled 4 receptor in a ligand-free state.,Yang S, Wu Y, Xu TH, de Waal PW, He Y, Pu M, Chen Y, DeBruine ZJ, Zhang B, Zaidi SA, Popov P, Guo Y, Han GW, Lu Y, Suino-Powell K, Dong S, Harikumar KG, Miller LJ, Katritch V, Xu HE, Shui W, Stevens RC, Melcher K, Zhao S, Xu F Nature. 2018 Aug;560(7720):666-670. doi: 10.1038/s41586-018-0447-x. Epub 2018 Aug, 22. PMID:30135577[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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