Abstract
Many new gene copies emerged by gene duplication in hominoids, but little is known with respect to their functional evolution. Glutamate dehydrogenase (GLUD) is an enzyme central to the glutamate and energy metabolism of the cell. In addition to the single, GLUD-encoding gene present in all mammals (GLUD1), humans and apes acquired a second GLUD gene (GLUD2) through retroduplication of GLUD1, which codes for an enzyme with unique, potentially brain-adapted properties. Here we show that whereas the GLUD1 parental protein localizes to mitochondria and the cytoplasm, GLUD2 is specifically targeted to mitochondria. Using evolutionary analysis and resurrected ancestral protein variants, we demonstrate that the enhanced mitochondrial targeting specificity of GLUD2 is due to a single positively selected glutamic acid-to-lysine substitution, which was fixed in the N-terminal mitochondrial targeting sequence (MTS) of GLUD2 soon after the duplication event in the hominoid ancestor ∼18–25 million years ago. This MTS substitution arose in parallel with two crucial adaptive amino acid changes in the enzyme and likely contributed to the functional adaptation of GLUD2 to the glutamate metabolism of the hominoid brain and other tissues. We suggest that rapid, selectively driven subcellular adaptation, as exemplified by GLUD2, represents a common route underlying the emergence of new gene functions.
Highlights
The process of gene duplication is the major mechanism underlying the origin of new gene functions and has significantly contributed to the emergence of adaptive evolutionary novelties during evolution [1,2]
It is encoded by the intronless GLUD2 gene, which emerged via the reverse transcription of a messenger RNA from its parental gene GLUD1 in the hominoid ancestor 18–25 million years ago (Mya) [7]
We show that whereas GLUD1 localizes to the mitochondria as well as the cytoplasm, GLUD2 is targeted to mitochondria, due to a single key amino acid substitution in its signal peptide, which emerged in the common hominoid ancestor and appears to have been fixed under the influence of positive selection
Summary
The process of gene duplication is the major mechanism underlying the origin of new gene functions and has significantly contributed to the emergence of adaptive evolutionary novelties during evolution [1,2]. Previous work showed that the GLUD2encoded enzyme evolved unique, potentially brain-specific functional properties soon after the duplication event by virtue of two key amino acid substitutions that were fixed as a result of positive selection [7,13]. Due to these substitutions, GLUD2 shows higher activity at neutral pH than GLUD1, is less sensitive to GTP inhibition, and—unlike GLUD1—requires high ADP levels for its allosteric activation [14]. The enhanced mitochondrial targeting capacity of GLUD2 probably reflects further selectively driven optimization of this enzyme to the
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