7mn8
Structure of the HER2/HER3/NRG1b Heterodimer Extracellular Domain bound to Trastuzumab Fab
Structural highlights
DiseaseERBB3_HUMAN Defects in ERBB3 are the cause of lethal congenital contracture syndrome type 2 (LCCS2) [MIM:607598; also called Israeli Bedouin multiple contracture syndrome type A. LCCS2 is an autosomal recessive neurogenic form of a neonatally lethal arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord. The LCCS2 syndrome is characterized by multiple joint contractures, anterior horn atrophy in the spinal cord, and a unique feature of a markedly distended urinary bladder. The phenotype suggests a spinal cord neuropathic etiology.[1] FunctionERBB3_HUMAN Binds and is activated by neuregulins and NTAK.[2] Publication Abstract from PubMedHuman epidermal growth factor receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex(1-3) upon binding of growth factor neuregulin-1beta (NRG1beta). The mechanism by which HER2 and HER3 interact remains unknown in the absence of any structures of the complex. Here we isolated the NRG1beta-bound near full-length HER2-HER3 dimer and, using cryo-electron microscopy, reconstructed the extracellulardomain module, revealing unexpected dynamics at the HER2-HER3 dimerization interface. We show that the dimerization arm of NRG1beta-bound HER3 is unresolved because the apo HER2 monomer does not undergo a ligand-induced conformational change needed to establish a HER3 dimerization arm-binding pocket. In a structure of the oncogenic extracellular domain mutant HER2(S310F), we observe a compensatory interaction with the HER3 dimerization arm that stabilizes the dimerization interface. Both HER2-HER3 and HER2(S310F)-HER3 retain the capacity to bind to the HER2-directed therapeutic antibody trastuzumab, but the mutant complex does not bind to pertuzumab. Our structure of the HER2(S310F)-HER3-NRG1beta-trastuzumab Fab complex reveals that the receptor dimer undergoes a conformational change to accommodate trastuzumab. Thus, similar to oncogenic mutations, therapeutic agents exploit the intrinsic dynamics of the HER2-HER3 heterodimer. The unique features of a singly liganded HER2-HER3 heterodimer underscore the allosteric sensing of ligand occupancy by the dimerization interface and explain why extracellular domains of HER2 do not homo-associate via a canonical active dimer interface. Structures of the HER2-HER3-NRG1beta complex reveal a dynamic dimer interface.,Diwanji D, Trenker R, Thaker TM, Wang F, Agard DA, Verba KA, Jura N Nature. 2021 Dec;600(7888):339-343. doi: 10.1038/s41586-021-04084-z. Epub 2021 , Nov 10. PMID:34759323[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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