Transfer RNA (tRNA) is a small, noncoding RNA that acts as an adaptor during translation, the process by which cells synthesize proteins. Each functional tRNA connects recognition of a sequence in messenger RNA (mRNA) with delivery of an amino acid to a ribosome. Its anticodon recognizes an mRNA codon, while its opposite end carries the amino acid incorporated into the growing protein. This division of functions provides a molecular link between the genetic code and the chemistry of protein synthesis. (ncbi.nlm.nih.gov)
Molecular structure
Most mature tRNAs contain approximately 70–90 nucleotides. Although each consists of a single RNA strand, complementary regions pair internally to form stems separated by loops. Their conventional secondary-structure diagram resembles a cloverleaf: an acceptor stem, a D arm, an anticodon arm, a T arm, and a variable region. The D and T arms take their names from characteristic modified nucleosides, dihydrouridine and ribothymidine, respectively; the T loop also commonly contains pseudouridine. (ncbi.nlm.nih.gov)
In three dimensions, interactions between these regions produce a compact L-shaped structure. The anticodon occupies one extremity, and the amino-acid attachment site occupies the other. This arrangement allows a tRNA to contact the ribosome’s decoding region and peptide-forming center simultaneously. Mature tRNAs normally terminate with the sequence CCA at their 3′ end; the terminal adenosine provides the attachment site for an amino acid. Some organellar tRNAs depart substantially from the canonical cloverleaf, including forms lacking an entire conventional arm. (ncbi.nlm.nih.gov)
Aminoacylation and molecular identity
Before participating in protein synthesis, a tRNA must be charged, or aminoacylated. An aminoacyl-tRNA synthetase uses adenosine triphosphate (ATP) to activate an amino acid and transfer it to the tRNA’s terminal adenosine. The amino acid’s carboxyl group forms an ester linkage with the terminal ribose. The resulting aminoacyl-tRNA carries both the amino acid and the activated linkage required for subsequent peptide synthesis. (ncbi.nlm.nih.gov)
A synthetase recognizes a combination of sequence and structural features rather than simply reading the anticodon. These identity elements may occur in the acceptor stem, anticodon, or other regions. For example, the G3–U70 base pair in alanine tRNA is a major determinant of recognition by alanyl-tRNA synthetase. Different tRNAs carrying the same amino acid are called isoacceptors; they can have different anticodons and decode different synonymous codons. (ncbi.nlm.nih.gov)
Many synthetases also possess editing activities that remove incorrectly activated or attached amino acids. These reactions are important because chemically similar amino acids can be difficult to discriminate. Accurate translation therefore depends on two distinct matching operations: attaching the correct amino acid to its tRNA and selecting that charged tRNA for the appropriate mRNA codon. (ncbi.nlm.nih.gov)
Anticodons and wobble
The anticodon is a three-nucleotide sequence exposed in the anticodon loop. It pairs antiparallel to the mRNA codon, so the anticodon’s 5′ nucleotide faces the codon’s third nucleotide. Pairing at this position can accommodate certain alternatives to standard Watson–Crick pairing, a phenomenon called wobble base pairing. Consequently, an individual tRNA can recognize more than one codon without changing which amino acid it supplies. (ncbi.nlm.nih.gov)
Wobble helps explain why cells do not require a separate tRNA species for every amino-acid-specifying codon. Modified anticodon nucleosides further influence which codons can be recognized and how accurately they are read. The flexibility is constrained by molecular geometry and nucleotide chemistry: it does not mean that arbitrary mismatches are accepted. (ncbi.nlm.nih.gov)
Participation in the ribosomal cycle
During elongation, a charged tRNA is delivered to the ribosome with an elongation factor. The ribosome evaluates codon–anticodon pairing at its A, or aminoacyl, site. Structural rearrangements and proofreading steps favor acceptance of a correctly matched tRNA over closely related alternatives. (nature.com)
The P, or peptidyl, site holds the tRNA carrying the growing peptide. Formation of a peptide bond transfers that peptide onto the amino acid attached to the A-site tRNA. The ribosomal catalytic center, formed principally by ribosomal RNA, positions the substrates for this reaction. The growing chain therefore becomes attached to the tRNA originally occupying the A site. (nature.com)
During translocation, mRNA and tRNAs move relative to the ribosome. The peptide-bearing tRNA advances toward the P site, while the deacylated tRNA moves toward the E, or exit, site and is released. Transitional hybrid states allow the two ends of a tRNA to occupy different binding-site positions on the ribosomal subunits. Released tRNAs can be charged again and reused. (nature.com)
Synthesis and maturation
tRNAs are encoded by genes in DNA and produced by transcription. Nuclear tRNA genes in eukaryotes are generally transcribed by RNA polymerase III. The initial transcripts are precursors rather than fully functional molecules: extra sequences at their ends must be removed, and some contain introns that require splicing. (ncbi.nlm.nih.gov)
Processing generates the mature termini, including the CCA tail, which may be encoded in the gene or added enzymatically. Chemical modification of selected nucleotides accompanies maturation. These modifications contribute to folding, stability, and decoding properties, so a mature tRNA’s chemical composition cannot always be inferred directly from its gene sequence. (pubmed.ncbi.nlm.nih.gov)
Historical investigation
In 1965, Robert W. Holley and colleagues published the complete nucleotide sequence of an alanine tRNA isolated from yeast—the first complete sequence established for a nucleic acid. Its internal complementarity supported the cloverleaf model of tRNA secondary structure. Holley shared the 1968 Nobel Prize in Physiology or Medicine with Har Gobind Khorana and Marshall Nirenberg for work interpreting the genetic code and its function in protein synthesis. (pubmed.ncbi.nlm.nih.gov)