Human selenocysteine synthase, SEPSECS, has evolved to optimize binding of a tRNA-based substrate

Area of Science:

• Biochemistry
• Molecular Biology
• Evolutionary Biology

Background:

• Selenocysteine (Sec) incorporation is vital for selenoproteome development across all life domains.
• O-phosphoseryl-tRNASec selenium transferase (SepSecS) is key to Sec synthesis in archaea and eukaryotes.
• Human SEPSECS exhibits asymmetric tRNA binding, with a C-terminal helix influencing complex stability.

Purpose of the Study:

• Investigate the evolutionary origins of the SEPSECS tRNA-binding mechanism.
• Determine the role of the C-terminal extension in SEPSECS function and regulation.
• Understand the differences in tRNA binding between mammalian and archaeal SEPSECS.

Main Methods:

• Comparative structural analysis of SEPSECS across species.
• Phylogenetic analysis to trace the evolution of tRNA-binding motifs.
• Biochemical assays to assess tRNA binding affinities and requirements.

Main Results:

• SEPSECS tRNA-binding motifs are poorly conserved across species.
• Archaeal SEPSECS requires an aminoacyl group for tRNA binding, unlike mammalian SEPSECS.
• The C-terminal α-helix 16 is a mammalian innovation that prevents aggregation at low tRNA concentrations.

Conclusions:

• SEPSECS evolved distinct tRNA-binding mechanisms across different domains of life.
• The mammalian C-terminal helix represents a regulatory innovation for SEPSECS function.
• These findings highlight the evolution of SEPSECS as a regulatory point for selenoprotein synthesis.