Related Experiment Video

Updated: Apr 18, 2026

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
15:05

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

9.5K

Molecular architecture of the ErbB2 extracellular domain homodimer

Shi Hu1,2,3,4, Yuna Sun2,3, Yanchun Meng5,6,7

  • 1International Joint Cancer Institute & Translational Medicine Research Institute, the Second Military Medical University, Shanghai, 200433, P.R. China.

Oncotarget
|January 31, 2015
PubMed

Insights

Researchers uncovered the unique homodimer structure of the ErbB2 extracellular domain, revealing a novel "back to head" interaction crucial for its signaling. This finding clarifies ErbB2 dimerization mechanisms and informs targeted cancer therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Human epidermal growth factor receptors (HERs or ErbBs) are vital for cellular processes.
  • ErbB2 overexpression is a common cancer abnormality linked to aggressive disease.
  • Dimer-dependent phosphorylation of ErbBs is critical for signal transduction, but ErbB2 dimerization mechanisms are unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism of ErbB2 homodimerization.
  • To characterize the unique structural architecture of the ErbB2 extracellular domain (ECD) homodimer.
  • To investigate the impact of this dimerization on ErbB2 signaling and therapeutic antibody targeting.

Main Methods:

  • X-ray crystallography to determine the structure of the ErbB2 ECD homodimer.
  • Site-directed mutagenesis to validate the dimer architecture and its functional consequences.
  • Biochemical assays to assess the impact of dimerization on ErbB2 phosphorylation.

Main Results:

  • The ErbB2 ECD forms a unique homodimer with a "back to head" interaction.
  • A protruding β-hairpin arm from domain II inserts into a pocket formed by domains I-III of the adjacent protomer.
  • Mutagenesis studies confirmed this architecture and its influence on intracellular domain phosphorylation.
  • The distinct impacts of trastuzumab and pertuzumab on ErbB2 dimerization were elucidated.

Conclusions:

  • The study reveals the unique homodimer architecture of the ErbB2 ECD.
  • This structural insight provides a molecular understanding of ErbB2 signaling and phosphorylation.
  • The findings offer a molecular basis for understanding ErbB2-targeted therapies, including antibody treatments.

More Related Videos

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay09:07

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay

Published on: December 19, 2018

6.9K
Dissecting Multi-protein Signaling Complexes by Bimolecular Complementation Affinity Purification BiCAP06:45

Dissecting Multi-protein Signaling Complexes by Bimolecular Complementation Affinity Purification BiCAP

Published on: June 15, 2018

8.0K

Related Concept Videos

Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
7.2K
Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
21.2K
Structure of Cadherins01:25

Structure of Cadherins

The cadherins were one of the first cell adhesion molecules discovered; the term “cadherins”   is based on their calcium-dependent adhering properties. The first cadherins discovered on the epithelial, neuronal, and placental cells were named E-cadherin, P-cadherin, and N-cadherin, respectively. These classical cadherins share sequence and structural similarities. Other cadherins, including those involved in cell signaling, are grouped into non-classical cadherins. This...
5.3K
Multi-pass Transmembrane Proteins and β-barrels01:09

Multi-pass Transmembrane Proteins and β-barrels

In multi-pass transmembrane proteins, the polypeptide chain crosses the membrane more than once. The transmembrane polypeptide chain either forms an α-helix or β-strand structure. α-Helix containing multi-pass transmembrane proteins are ubiquitous, whereas β-strand containing ones are mainly found in gram-negative bacteria, mitochondria, and chloroplasts.
α-Helix containing multi-pass transmembrane proteins
Multi-pass transmembrane proteins such as...
6.9K
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
3.0K
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
5.1K