On elongation factor eEFSec,its role and mechanism during selenium incorporation into nascent selenoproteins

Background

Selenium, an essential dietary micronutrient, is incorporated into proteins as the amino acid selenocysteine (Sec) in response to in-frame UGA codons. Complex machinery ensures accurate recoding of Sec codons in higher organisms. A specialized elongation factor eEFSec is central to the process.

Scope of review

Selenoprotein synthesis relies on selenocysteinyl-tRNA^Sec (Sec-tRNA^Sec), selenocysteine inserting sequence (SECIS) and other selenoprotein mRNA elements, an in-trans SECIS binding protein 2 (SBP2) protein factor, and eEFSec. The exact mechanisms of discrete steps of the Sec UGA recoding are not well understood. However, recent studies on mammalian model systems have revealed the first insights into these mechanisms. Herein, we summarize the current knowledge about the structure and role of mammalian eEFSec.

Major conclusions

eEFSec folds into a chalice-like structure resembling that of the archaeal and bacterial orthologues SelB and the initiation protein factor IF2/eIF5B. The three N-terminal domains harbor major functional sites and adopt an EF-Tu-like fold. The C-terminal domain 4 binds to Sec-tRNA^Sec and SBP2, senses distinct binding domains, and modulates the GTPase activity. Remarkably, GTP hydrolysis does not induce a canonical conformational change in eEFSec, but instead promotes a slight ratchet of domains 1 and 2 and a lever-like movement of domain 4, which may be critical for the release of Sec-tRNA^Sec on the ribosome.

General significance

Based on current findings, a non-canonical mechanism for elongation of selenoprotein synthesis at the Sec UGA codon is proposed. Although incomplete, our understanding of this fundamental biological process is significantly improved, and it is being harnessed for biomedical and synthetic biology initiatives. This article is part of a Special Issue entitled “Selenium research” in celebration of 200 years of selenium discovery, edited by Dr. Elias Arnér and Dr. Regina Brigelius-Flohe.