Heterohexamers

Heterohexamers are protein complexes made up of six subunits in which not all subunits are identical. At least two distinct subunit types are present, yielding a stoichiometry that typically involves three copies of one subunit and three copies of another, or other combinations that include more than one type. This contrasts with homohexamers, which contain six identical subunits.

Structurally, heterohexamers often form ring- or collar-like assemblies in which the different subunits interact at specific interfaces to create a functional whole. The presence of multiple subunit types can enable distinct active sites, regulatory contacts, or binding surfaces, and the arrangement of subunits can influence symmetry, cooperativity, and stability. Assembly is usually governed by complementary interfaces and precise subunit ratios.

A well-known example is the catalytic core of bacterial F1-ATP synthase, which forms an α3β3 hexamer with alternating alpha and beta subunits arranged around a central stalk. This heterohexamer arrangement is central to the enzyme’s rotary catalysis and regulation. Other heterohexameric assemblies are found in signaling and metabolic contexts, where different subunits contribute specialized functions or regulatory properties.

Studying heterohexamers combines biochemical purification, mass spectrometry to determine composition, and structural methods such as X-ray crystallography or cryo-electron microscopy to resolve subunit arrangement. Native mass spectrometry and cross-linking approaches can help confirm stoichiometry and interfaces, while mutational analyses reveal the roles of specific subunit contacts.

Significance lies in how subunit diversity within a six-subunit complex enables coordinated activity, allosteric regulation, and functional specialization that single-subunit types could not achieve.