heteromerization

Heteromerization refers to the assembly of two or more non-identical subunits into a single functional complex, called a heteromer. This contrasts with homomerization, where identical subunits form a complex. Heteromer formation is a common mechanism to expand functional diversity, regulate localization, and modify biochemical properties across many protein families, including receptors, ion channels, transporters, and signaling kinases.

In G protein-coupled receptors, heteromerization is well documented and can create receptors with distinct ligand affinity, G protein coupling, and downstream signaling. Examples include the dopamine D1-D2 heteromer and the adenosine A2A-D2 heteromer, which exhibit unique pharmacology not predicted by their individual members. The GABAB receptor is often cited as an obligate heterodimer of GB1 and GB2, each subunit contributing different functional roles.

Ion channels and transporter proteins also form heteromeric assemblies. NMDA receptors are heterotetramers typically composed of NR1 and NR2 subunits, with subunit composition shaping gating, conductance, and pharmacology. Other channels use diverse subunit assemblies to create distinct channel properties. Receptor tyrosine kinases can form heterodimers that modulate ligand binding and signaling, providing combinatorial diversity in activation and downstream pathways.

Evidence for heteromerization comes from biochemical and biophysical approaches such as co-immunoprecipitation, fluorescence resonance energy transfer and bioluminescence resonance energy transfer (FRET/BRET), proximity ligation assays, and cross-linking experiments, as well as structural methods like cryo-electron microscopy. Functional studies comparing heteromer versus homomer signaling help establish physiological relevance.

Because heteromerization can alter trafficking, ligand sensitivity, and signal bias, it has implications for pharmacology and drug discovery. Targeting specific heteromers offers therapeutic potential but poses challenges for selectivity and in vivo validation, given the dynamic and context-dependent nature of subunit assembly.