Abstract
Proteins assemble into complexes with diverse quaternary structures. Although most heteromeric complexes of known structure have even stoichiometry, a significant minority have uneven stoichiometry--that is, differing numbers of each subunit type. To adopt this uneven stoichiometry, sequence-identical subunits must be asymmetric with respect to each other, forming different interactions within the complex. Here we first investigate the occurrence of uneven stoichiometry, demonstrating that it is common in vitro and is likely to be common in vivo. Next, we elucidate the structural determinants of uneven stoichiometry, identifying six different mechanisms by which it can be achieved. Finally, we study the frequency of uneven stoichiometry across evolution, observing a significant enrichment in bacteria compared with eukaryotes. We show that this arises due to a general increased tendency for bacterial proteins to self-assemble and form homomeric interactions, even within the context of a heteromeric complex.
Highlights
IntroductionMost heteromeric complexes of known structure have even stoichiometry, a significant minority have uneven stoichiometry—that is, differing numbers of each subunit type
Proteins assemble into complexes with diverse quaternary structures
We plot the percentages of complexes with uneven stoichiometry for heteromers with varying numbers of distinct subunit types (Fig. 2a)
Summary
Most heteromeric complexes of known structure have even stoichiometry, a significant minority have uneven stoichiometry—that is, differing numbers of each subunit type. We study the frequency of uneven stoichiometry across evolution, observing a significant enrichment in bacteria compared with eukaryotes We show that this arises due to a general increased tendency for bacterial proteins to self-assemble and form homomeric interactions, even within the context of a heteromeric complex. Any heteromer that has uneven subunit stoichiometry (that is, 2:1 or 3:1) will inherently have some degree of asymmetry This is because, to assemble a complex with uneven stoichiometry, different subunits of the same type must necessarily exist in different local environments. As each H subunit interacts with a different region on the L subunit, they are in non-equivalent positions within the complex
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