8u4j

Structure of the HER4/BTC Homodimer Extracellular Domain

spinqualitylabelsall models 8u4j, resolution 3.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8u4j is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.7Å Ligands: BMA, MAN, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function BTC_HUMAN Growth factor that binds to EGFR, ERBB4 and other EGF receptor family members. Potent mitogen for retinal pigment epithelial cells and vascular smooth muscle cells. Publication Abstract from PubMed Human Epidermal growth factor Receptor 4 (HER4 or ERBB4) carries out essential functions in the development and maintenance of the cardiovascular and nervous systems. HER4 activation is regulated by a diverse group of extracellular ligands including the neuregulin (NRG) family and betacellulin (BTC), which promote HER4 homodimerization or heterodimerization with other HER receptors. Important cardiovascular functions of HER4 are exerted via heterodimerization with its close homolog and orphan receptor, HER2. To date structural insights into ligand-mediated HER4 activation have been limited to crystallographic studies of HER4 ectodomain homodimers in complex with NRG1beta. Here, we report cryo-EM structures of near full-length HER2/HER4 heterodimers and full-length HER4 homodimers bound to NRG1beta and BTC. We show that the structures of the heterodimers bound to either ligand are nearly identical and that in both cases the HER2/HER4 heterodimer interface is less dynamic than those observed in structures of HER2/EGFR and HER2/HER3 heterodimers. In contrast, structures of full-length HER4 homodimers bound to NRG1beta and BTC display more large-scale dynamics mirroring states previously reported for EGFR homodimers. Our structures also reveal the presence of multiple glycan modifications within HER4 ectodomains, modeled for the first time in HER receptors, that distinctively contribute to the stabilization of HER4 homodimer interfaces over those of HER2/HER4 heterodimers. Structural dynamics of the active HER4 and HER2/HER4 complexes is finely tuned by different growth factors and glycosylation.,Trenker R, Diwanji D, Bingham T, Verba KA, Jura N Elife. 2024 Mar 18;12:RP92873. doi: 10.7554/eLife.92873. PMID:38498590 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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