heterooligomerization

Heterooligomerization is the assembly of protein complexes from different subunits, resulting in an oligomer that contains more than one distinct polypeptide. This contrasts with homooligomerization, in which all subunits are identical. Heterooligomeric assemblies are common among receptors, ion channels, transporters, and signaling enzymes, and can include dimers, trimers, tetramers, or larger complexes. The specific subunit composition can determine functional properties such as ligand binding, gating, trafficking, and regulation.

Well-studied examples include the NMDA receptor in neurons, which forms heterotetramers usually composed of NR1 and NR2 subunits; GABA-B receptors, which require GB1 and GB2 subunits to function; and nicotinic acetylcholine receptors that assemble with multiple subunit types to yield channels with distinct conductance and pharmacology. Other ion channels and transporters also rely on heteromeric subunits to modulate kinetics and regulation. In some cases, heterooligomerization creates tissue-specific receptor subtypes from a common subunit repertoire.

Biological significance and regulation: The subunit composition shapes ligand affinity, ion selectivity, signaling coupling, surface expression, and desensitization. It allows tissues to customize signaling responses without expanding the genome. Assembly occurs in the endoplasmic reticulum and Golgi, often requiring chaperones and quality-control mechanisms; misassembly can trigger degradation. Subunit competition and expression dynamics can shift stoichiometry and function over development or disease.

Methods to study heterooligomerization include co-immunoprecipitation, resonance energy transfer techniques (FRET or BRET), cross-linking, blue native PAGE, and mass spectrometry-based proteomics. High-resolution structural methods, such as cryo-electron microscopy, reveal subunit interfaces and assembly symmetry, contributing to understanding of pharmacology and selective targeting.