Human epidermal growth factor receptor 2 extracellular domain subdomain I (HER2 ECD Subdomain I)

The Human Epidermal Growth Factor Receptor 2 (HER2) extracellular domain (ECD) subdomain I is a leucine-rich region located at the N-terminus of the HER2 protein [NIH, 2024]. Unlike other members of the EGFR family, HER2 exists in a constitutively "open" or extended conformation and has no known high-affinity ligand [NIH, 2024; AACR, 2015]. Subdomain I, also referred to as the L1 domain, plays a critical structural role in maintaining this active-like state by interacting with subdomain III, which prevents the receptor from adopting the "tethered" inactive conformation seen in EGFR or HER3 [NIH, 2024]. This unique structural arrangement makes HER2 the preferred dimerization partner for other ligand-activated ErbB receptors, driving potent downstream signaling through the PI3K/AKT and MAPK pathways that promote cell proliferation and survival [NIH, 2024; Encyclopedia Pub, 2023]. While established clinical therapies like trastuzumab and pertuzumab target subdomains IV and II respectively, subdomain I is an emerging target for next-generation therapeutics, including experimental antibodies like A21 and various multi-epitope mixtures [AACR, 2015; RCSB, 2006]. These novel agents are designed to induce receptor internalization or block dimerization more effectively than current treatments, offering potential strategies to overcome therapeutic resistance in HER2-positive cancers [AACR, 2015; Biosensing USA, 2024].

Other names

ErbB2 subdomain IHER2 domain IL1 domain of HER2CD340 subdomain Ip185erbB2 subdomain INeuro/glioblastoma-derived oncogene homolog subdomain I

Antibodies or binders targeting subdomain I typically function by inducing receptor internalization and degradation, or by sterically hindering the formation of signaling-active dimers, thereby inhibiting downstream oncogenic pathways such as PI3K/AKT and MAPK/ERK [AACR, 2015; NIH, 2024].