8U4K

Structure of the HER2/HER4/BTC Heterodimer Extracellular Domain

Summary for 8U4K

• Entry DOI: 10.2210/pdb8u4k/pdb
• EMDB information: 41883 41884 41885 41886
• Descriptor: Isoform JM-A CYT-1 of Receptor tyrosine-protein kinase erbB-4, Receptor tyrosine-protein kinase erbB-2, Betacellulin, ... (9 entities in total)
• Functional Keywords: receptor tyrosine kinase, membrane protein, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 147281.49

Authors

Trenker, R.,Diwanji, D.,Bingham, T.,Verba, K.A.,Jura, N. (deposition date: 2023-09-10, release date: 2024-03-13, Last modification date: 2024-10-30)

Primary citation

Trenker, R.,Diwanji, D.,Bingham, T.,Verba, K.A.,Jura, N.
Structural dynamics of the active HER4 and HER2/HER4 complexes is finely tuned by different growth factors and glycosylation.
Elife, 12:-, 2024

PubMed Abstract: 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 NRG1β. Here, we report cryo-EM structures of near full-length HER2/HER4 heterodimers and full-length HER4 homodimers bound to NRG1β 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 NRG1β 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.

PubMed: 38498590
DOI: 10.7554/eLife.92873

Experimental method

ELECTRON MICROSCOPY (4.27 Å)