Heterodimer

A heterodimer is a protein complex formed by two different polypeptide chains that associate to perform a biological function. The two subunits are non-identical, distinguishing heterodimers from homodimers, which consist of two identical subunits.

Subunit interaction is typically non-covalent and stabilized by hydrophobic contacts, hydrogen bonds, and ionic interactions, though some heterodimers are held together by covalent disulfide bonds. The interface between subunits often dictates the complex’s specificity and regulatory properties.

Heterodimers are widespread in biology. In transcription, dimerization of different basic leucine zipper (bZIP) or helix–loop–helix proteins expands the repertoire of DNA-binding activities, as seen with AP-1 (c-Fos and c-Jun). In cell signaling, receptor and kinase subunits frequently pair with distinct partners, creating diverse signaling outputs. They also occur in signaling networks involving G protein-coupled receptors and other membrane-associated complexes, where different subunits modulate activity and ligand sensitivity.

Functional consequences include expanded binding specificity, altered activity, and refined regulation. Heterodimer formation can enable tissue-specific responses and developmental control. Misregulation of subunit pairing is implicated in diseases and is a target for therapeutic strategies that disrupt or stabilize specific interfaces.

Techniques to study heterodimers include yeast two-hybrid screens, co-immunoprecipitation, cross-linking, Förster resonance energy transfer (FRET), and mass spectrometry-based approaches. Structural methods such as X-ray crystallography and cryo-electron microscopy reveal the architecture of the dimer and its interaction surfaces.