Co-translational assembly promotes functional diversification of paralogous proteins

Abstract

Homomeric proteins are ubiquitous and mediate myriads of cellular functions. When a gene encoding a homomer duplicates, the resulting paralogs can either form distinct homomers, or evolve into a heteromer containing both paralogs. While such events have extensively shaped proteomes, the molecular mechanisms driving these fates and their associated functional consequences remain largely unknown. Here, we conducted a comprehensive phylogenomic analysis tracing gene duplication histories of 7,377 human paralogs across the eukaryotic lineage and identified their fates using protein interaction data. Simulations and data analyses show that cellular constraints must act as barriers to disfavor heteromerization and promote homomerization. We found that multiple cellular and molecular constraints can serve as barriers, including the lack of co-expression and co-localization. The main barrier, however, is co-translational assembly, which naturally promotes the self-assembly of each paralog from its corresponding mRNA, thus hindering heteromerization. We further established that heteromerization constrains functional divergence, with homomeric paralogs exhibiting stronger signatures of adaptive evolution and functional divergence compared to heteromeric paralogs. Together, these findings identify key biochemical and cellular properties that explain protein function diversification following gene duplication. One Sentence SummaryCo-translational assembly drives the selective homo-oligomerization of paralogs, which in turn promotes their functional divergence. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=180 HEIGHT=200 SRC="FIGDIR/small/634331v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@b17418org.highwire.dtl.DTLVardef@3d0a61org.highwire.dtl.DTLVardef@1747aeaorg.highwire.dtl.DTLVardef@31b931_HPS_FORMAT_FIGEXP M_FIG C_FIG