Heterodimers

A heterodimer is a protein complex formed by two different polypeptide chains that associate to produce a functional unit. Unlike homodimers, in which two identical subunits come together, heterodimers expand the functional possibilities of proteins by combining distinct subunits that can contribute different DNA-binding specificities, catalytic activities, or regulatory properties. Heterodimers are common in diverse cellular processes, including transcription regulation, signal transduction, and metabolism.

In transcription factors, heterodimers such as AP-1 (Fos-Jun) pair different subunits to modulate gene expression. Nuclear receptors frequently function as obligate heterodimers; for example, RXR forms partners with PPARs, LXR, and RAR to regulate lipid metabolism and development. G protein-coupled receptors can also form heterodimers, which may alter ligand affinity and signaling outcomes; the GABA-B receptor is a notable example, requiring GABA-B1 and GABA-B2 subunits for proper trafficking and activity.

Formation and structure: heterodimers are stabilized by non-covalent interactions at specific dimerization interfaces, often involving coiled-coil or helix-loop-helix motifs. The interface determines specificity and stability, and some heterodimers are obligatorily formed, whereas others can also assemble into homodimers. The ability to pair with different partners increases functional repertoire beyond what a single subunit could achieve.

Detection and significance: heterodimers are studied via methods such as yeast two-hybrid screens, co-immunoprecipitation, cross-linking, and mass spectrometry, with structural insights from X-ray crystallography or cryo-electron microscopy. Dysregulation of heterodimer formation or function is linked to diseases including cancer, metabolic disorders, and developmental abnormalities, making understanding heterodimer interfaces relevant for targeted drug design.