heterodimerisation

Heterodimerisation refers to the association of two different subunits to form a heterodimer, a molecular complex in which two distinct polypeptides cooperate to perform biological functions. Most commonly observed in proteins, heterodimers arise through non-covalent interactions at complementary surfaces, though rare covalent linkages have been reported. This process expands functional diversity beyond homodimers, enabling new substrate specificities, regulatory properties, and signaling outputs.

Heterodimer formation can be constitutive or regulated by ligands, phosphorylation, or other modifications that alter interface affinity or subcellular localization. Structural motifs such as leucine zippers, coiled-coil domains, helix–loop–helix regions, and hinge or dimerization domains contribute to partner selectivity and stability. In transcriptional regulation, heterodimers often alter DNA-binding specificity and transcriptional activity. In signaling receptors, heterodimerisation can create novel ligand-binding pockets or signaling capabilities, sometimes converting a mono-specific receptor into a multi-functional complex.

Nuclear receptor heterodimers with retinoid X receptor (RXR) are classic examples; PPARs, the vitamin D receptor (VDR), and others commonly pair with RXR to regulate gene expression. Another well-known example is the heterodimeric transcription factor AP-1, composed of Jun and Fos family members, which can function as a heterodimer with distinct regulatory properties.

Techniques to study heterodimerisation include co-immunoprecipitation, pull-down assays, yeast two-hybrid screens, and biophysical approaches such as FRET or BRET, as well as structural methods like X-ray crystallography or cryo-EM.

Biological and medical relevance stems from the role of heterodimers in development, immune function, metabolism, and disease, and they are targets for therapeutic intervention in some contexts.