Human epidermal growth factor receptor 2 dimerization interface (HER2 dimerization interface)

The **HER2 dimerization interface** refers to specific structural regions on the extracellular domain of the human epidermal growth factor receptor 2 (HER2, also known as ERBB2) that mediate receptor dimerization, a prerequisite for activation of HER2 signaling. Unlike other HER family receptors, HER2 has no known ligand and is generally activated by forming heterodimers with other HER receptors such as HER3 or HER4. The dimerization interface, mainly involving domain II (the 'dimerization arm') of HER2, is crucial for transmitting growth and survival signals downstream. Structural studies show that in HER2/HER3 and HER2/HER4 heterodimers, the contribution and dynamics of each receptor's dimerization arm differ, influencing receptor activation and drug sensitivity[1][3][5]. Therapeutic antibodies such as pertuzumab specifically target the dimerization interface, blocking receptor-receptor contacts and thus inhibiting downstream oncogenic signaling, making this interface a key therapeutic target in HER2-positive cancers[1][2]. Overexpression or mutation at this interface can lead to aberrant activation and drive cancers such as breast and gastric carcinoma[1][2]. Safety considerations for drugs targeting this interface include cardiotoxicity and resistance due to mutations at the dimerization region or compensatory signaling in the HER network[2].

Other names

HER2 extracellular domain dimerization interfaceHER2/HER3 dimer interfaceHER2/HER4 dimer interfaceERBB2 dimerization interface

Monoclonal antibody inhibition of dimerization (e.g., pertuzumab sterically hinders the dimerization interface); Antibody-dependent cellular cytotoxicity (ADCC, e.g., trastuzumab); Inhibition of receptor activation and downstream signaling; Small molecule tyrosine kinase inhibition