Determining the interaction status and evolutionary fate of duplicated homomeric proteins

Abstract

Oligomeric proteins are central to life. Duplication and divergence of their genes is a key evolutionary driver, also because duplications can yield very different outcomes. Given a homomeric ancestor, duplication can yield two paralogs that form two distinct homomeric complexes, or a heteromeric complex comprising both paralogs. Alternatively, one paralog remains a homomer while the other acquires a new partner. However, so far, conflicting trends have been noted with respect to which fate dominates, primarily because different methods and criteria are being used to assign the interaction status of paralogs. Here, we systematically analyzed all Saccharomyces cerevisiae and Escherichia coli oligomeric complexes that include paralogous proteins. We found that the proportions of homo-hetero duplication fates strongly depend on a variety of factors, yet that nonetheless, rigorous filtering gives a consistent picture. In E. coli about 50%, of the paralogous pairs appear to have retained the ancestral homomeric interaction, whereas in S. cerevisiae only~10% retained a homomeric state. This difference was also observed when unique complexes were counted instead of paralogous gene pairs. We further show that this difference is accounted for by multiple cases of heteromeric yeast complexes that share common ancestry with homomeric bacterial complexes. Our analysis settles contradicting trends and conflicting previous analyses, and provides a systematic and rigorous pipeline for delineating the fate of duplicated oligomers in any organism for which protein-protein interaction data are available.

Structure of the Commander endosomal trafficking complex linked to X-linked intellectual disability/Ritscher-Schinzel syndrome

“…It has previously been proposed that the sequence divergence in the N-terminal HN domains could allow for distinct interactions amongst the family members, for example with the NF-κB complex (37, 44), and actin and microtubule cytoskeletal components (83). More generally, while many different protein families have evolved the ability to form multimeric ring structures, this most commonly involves homomeric symmetric interactions with one or a few repeated protein subunits (84–86). Heteromeric pseudo-symmetric structures composed of multiple paralogous proteins as seen for the COMMD decamer are less common, and typically arise from multiple gene duplication events.…”

“…More generally, while many different protein families have evolved the ability to form multimeric ring structures, this most commonly involves homomeric symmetric interactions with one or a few repeated protein subunits (84)(85)(86). Heteromeric pseudo-symmetric structures composed of multiple paralogous proteins as seen for the COMMD decamer are less common, and typically arise from multiple gene duplication events.…”

Compensatory mutations potentiate constructive neutral evolution by gene duplication

“…To generate N-terminal tagged variant alleles, we used a fusion PCR approach similar to our previous work (11). We first amplified both DHFR fragments from genomic DNA of strain s_167 (using oligo_238) and s_168 for (using oligo_239) for DHFR F [1,2] and DHFR F [3] respectively. The amplicons were flanked in 5prime with homology the the FCY1 promoter and with the DHFR linker in 3-prime (GGGGS repeats).…”

“…We then fused these amplicons in a second PCR reaction, and used these tagged alleles as donor in a CRISPR transformation using our standard protocol. We transformed MATa strains with the DHFR [1,2] tagged alleles and MATα strains with the DHFR [3] tagged alleles.…”

Inter-paralog amino acid inversion events in large phylogenies of duplicated proteins

“…After gene duplication, two proteins follow a semi-independent evolution. For example, before diverging, the two duplicates may influence each other by gene conversion [ 7 ] or homomeric-heteromeric interactions [ 8 ], and they tend to diversify in the expression profile [ 9 , 10 ]. Gene duplication is prevalent in all domains of life [ 11 ], and often the duplicated proteins are reported to go through functional diversification [ 12 ].…”