Scientists clarify structural basis for biosynthesis of mysterious 21st amino acid

One of the most remarkable aspects of translation, the process whereby genetic information is converted into proteins in cells, is its universality: nucleotide triplets ("codons") encode a set of twenty amino acids that form the building blocks for all living organisms. Selenocysteine, the "21^st amino acid" whose antioxidant properties help prevent cellular damage, is a rare exception to this rule. Structurally similar to the amino acid serine (Ser) but with an oxygen atom replaced by the micronutrient selenium (Se), selenocysteine is synthesized through a complex juggling of the cell's translational machinery whose mechanisms remain poorly understood.

Central to this multi-step process is a Sec-specific transfer RNA (tRNA^Sec) with an unusual structure that enables it to hijack the "stop codon" UGA to allow incorporation of selenocysteine during protein synthesis. In earlier work, the researchers identified features of tRNA^Sec that differentiate it from other tRNA, notably the peculiar structure of a domain called the D-arm, which appeared to act as an identification marker for recognition by the selenocysteine synthesis machinery. This time, the team analyzed the D-arm's role in the interaction of tRNA^Sec with O-phosphoseryl-tRNA kinase (PSTK), a protein whose selective phosphorylation is essential for selenocysteine encoding.

Using X-ray crystallography, the team showed for the first time that it is the unique structure of the tRNA^Sec D-arm which enables PSTK to distinguish tRNA^Sec from other tRNA. Reported in the August 13 issue of Molecular Cell (online August 12), the discovery clarifies a pivotal step in selenocysteine biosynthesis, shedding new light on the mysterious 21^st amino acid and the elaborate process by which it is created.