How gene duplication diversifies the landscape of protein oligomeric state and function

Abstract

Oligomeric proteins are central to cellular life and the duplication and divergence of their genes is a key driver of evolutionary innovations. The duplication of a gene coding for an oligomeric protein has numerous possible outcomes, which motivates questions on the relationship between structural and functional divergence. How do protein oligomeric states diversify after gene duplication? In the simple case of duplication of a homo-oligomeric protein gene, what properties can influence the fate of descendant paralogs toward forming independent homomers or maintaining their interaction as a complex? Furthermore, how are functional innovations associated with the diversification of oligomeric states? Here, we review recent literature and present specific examples in an attempt to illustrate and answer these questions.

Figure 1

Evolution of oligomeric state among homomeric proteins upon gene duplication. (a) Duplication of a gene encoding a homomeric protein. Before divergence, interfaces are compatible, so a mixture of homo- and heteromeric complexes can coexist. As the two copies diverge, three outcomes may follow: (i) each duplicate self-interacts, which we refer to as “Obligate homomers”. (ii) Both duplicates can interact to form a heteromeric complex that we refer to as “Obligate heteromer”. (iii) The duplicates follow different paths, with, for example, one copy remaining a homomer, while the other gains a new interaction. (b) The relative frequency of the four different outcomes as observed in an analysis of E. coli and S. cerevisiae’s interaction networks . Homomeric interactions are dominant in E. coli, whereas cross-reacting paralogs are dominant in S. cerevisiae. (c) After duplication of a gene coding for a homomeric protein, the two paralogs can fix as an Obligate heteromeric complex. Following such an event, further duplications events may expand the family. (d) Gene duplication of ring-like homomers often involves the paralogous copies co-assembling into the same ring, making the ring heteromeric.

Figure 2

Origins of interaction divergence between paralogs. (a) Incompatibility may emerge from different subcellular localization of the paralogous copies, such as the case of yeast Obligate homomers TRR1 (PDB code 3DX8) and TRR2 (UniProt code P38816). (b) Insertions and deletions at the interface can drive incompatibility, as in the case of yeast MAS1/2 heterodimer where an insertion (Ile42–Thr45) in MAS1 appears to block its self-interaction. In another example, two insertions, Gln211–Asp231 and Asp299–Thr365, appear to hinder filament formation of ARP4, which instead heteromerizes with its paralog ACT1. Here, the structure depicts an ACT1 filament (white, PDB code 6BNO) onto which ARP4 (purple, PDB code 5NBM) was superposed. (c) The gain/loss of the domain mediating the ancestral homomeric interaction is another mechanism for incompatibility. Such a scenario is seen in Obligate homomers GAL10 (PDB code 1Z45) and YNR071C (PDB code 1YGA). (d) Accumulation of amino acid substitutions can alter the interface specificity and bring about incompatibility. This scenario occurs in the yeast heteromer IDH1/2 (PDB code 3BLV). We note that the IDH complex shows A4B4 stoichiometry and only half of the complex (A2B2) is shown here for simplicity. The physiological relevance of the quaternary structures highlighted in this figure was inferred based on annotations from the QSBIO.org database .

Figure 3

Evolution of the oligomeric state in connection to functional innovations after gene duplication. (a) The duplication of a homomer yields two independent Obligate homomers sharing the same primary function but different localizations: yeast ALT1 (mitochondrial) and ALT2 (cytosolic). (b) The duplication of a homomer yields two independent Obligate homomers exhibiting different primary functions: E. coli LACA and MAA. The former is specific for acetylation of galactosyl units , while the latter catalyzes acetylation of glucosyl units . (c)Obligate heteromers with independent active sites can retain the ancestral function (white star), or maintain the function through additional subunits. In the case of yeast IDH1/2 heteromer, IDH1 has lost its catalytic activity and became a regulatory subunit . In the case of the exosome, all paralogs forming the PH ring lost the RNAse activity and a new subunit assumed that function. (d) Among Obligate heteromers where the active site is contributed by both subunits, both subunits are expected to maintain their function. In this case, regulatory activities may emerge in a separate domain, as in the case of yeast PFK1/2 heteromer . In a different scenario, an Obligate heteromer such as the yeast SPOTS complex recruits new regulatory subunits.