heterodimerization

Heterodimerization is the process by which two distinct protein subunits associate to form a dimer. The resulting heterodimer contains two different polypeptide chains encoded by separate genes, and it often exhibits properties that differ from those of homodimers composed of identical subunits.

Common in transcription factors, receptors, enzymes and signaling scaffolds, heterodimerization can influence DNA recognition, catalytic activity, stability, localization, and regulatory interactions. Classic examples include transcription factors from the basic helix-loop-helix family, such as MyoD and E12 (or E47) forming a heterodimer required for myogenic differentiation, and the MYC/MAX complex whose DNA binding and transcriptional activity depend on heterodimer formation. In receptor signaling, members of the receptor tyrosine kinase family (for example EGFR/HER2) can form heterodimers that modulate ligand affinity and downstream signaling.

Nuclear receptors often function as heterodimers; retinoid X receptor (RXR) commonly dimerizes with other receptors like PPARs, LXR and RAR, broadening ligand responsiveness.

Mechanistically, dimerization is typically facilitated by shared interaction domains such as coiled-coils, leucine zippers, or SH2/SH3 interfaces, and can be influenced by ligands, phosphorylation, or scaffolding proteins.

Functional consequences include expanded binding specificity, altered activity, changes in subcellular localization, and integrated signaling outputs. Dysregulation of heterodimerization is associated with diseases including cancer and metabolic disorders, and it can be targeted pharmacologically or exploited in synthetic biology to control protein interactions.

Methods to study heterodimers include co-immunoprecipitation, yeast two-hybrid assays, fluorescence resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET), and cross-linking mass spectrometry.