Mechanisms of Translational Control

This work employs structural and biophysical approaches to investigate the fundamental mechanisms of translational control in ribosomes. Specifically, we examine the molecular basis of Sec stop codon suppression and insertion, as well as the phenotypic consequences of perturbations to this process. Additionally, we explore how ribosome-binding antibiotics, particularly the pleuromutilin and aminoglycoside classes, affect translation initiation and termination, integrating high-resolution ribosome structures with microbiological and biochemical analyses. First, we used cryo-electron microscopy (cryo-EM) combined with biochemical assays to elucidate the mechanism of Sec recoding in the mammalian ribosome. Suppression of UGA is achieved through a complex involving the mRNA 3′ untranslated region (UTR) Sec insertion sequence (SECIS), SECIS-binding protein 2 (SBP2), the 40S ribosomal subunit, and tRNASec bound to eukaryotic elongation factor selenocysteine (eEFSec). Our results reveal a mechanism of Sec UGA recoding in eukaryotes that differs fundamentally from its prokaryotic counterpart. Next, we investigated the consequences of inefficient Sec incorporation on human health. O-phosphoseryl-tRNASec selenium transferase (SEPSECS), an enzyme essential for maintaining the cellular selenoproteome, catalyzes the terminal step in selenocysteine synthesis. Autosomal recessive mutations throughout SEPSECS lead to reduced selenoprotein levels and cause progressive cerebello-cerebral atrophy (PCCA) in humans. We conducted detailed biochemical, functional, and structural analyses of 12 pathogenic SEPSECS variants. Our results provide an improved framework for understanding SEPSECS-related neurodegeneration and may aid in defining the role of selenoproteins in central nervous system development and maintenance.

Author dc:creator

• Benjamin Killam (23292136)

• Biology
• Molecular

Statement dc:rights

• In Copyright
• Open Access after 2028-01-01

DOI dc:identifier

https://doi.org/10.25417/uic.31451884.v1

OAI identifier oai:identifier

oai:figshare.com:article/31451884