Heteromultimers

Heteromultimers are multimeric protein complexes assembled from different polypeptide subunits, as opposed to homomultimers that use identical subunits. The term is used across disciplines to describe receptors, transporters, enzymes, and structural assemblies in which subunit identity and arrangement determine properties such as ligand affinity, ion selectivity, and regulatory behavior.

Classic examples include hemoglobin, a heterotetramer of two alpha and two beta chains; NMDA-type glutamate receptors, typically composed of NR1 and NR2 subunits; GABA A receptors with diverse subunit compositions; nicotinic acetylcholine receptors with combinations like alpha4beta2; and various heteromeric potassium channels.

Subunit assembly is typically cotranslational or assisted by chaperones in the endoplasmic reticulum. Stoichiometry and subunit arrangement influence functional states and allosteric regulation. Evolutionarily, gene duplication followed by divergence has produced subunits that pair specifically, enabling tissue-specific signaling networks.

Detection and analysis rely on biochemical and biophysical methods such as co-immunoprecipitation, cross-linking coupled to mass spectrometry, Förster resonance energy transfer, and high-resolution cryo-electron microscopy. Functional studies use ligand binding assays, electrophysiology, and activity measurements to map subunit-dependent properties.

Understanding heteromultimers has implications for physiology and medicine, as altered subunit composition or misassembly can contribute to diseases and influence drug responses, making heteromultimers important pharmacological targets.