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FIGURE 5 Translation. A molecule of transfer RNA (tRNA), charged with its specific amino acid, phenylalanine (Phe), and already linked to the growing peptide chain, is positioned on the mRNA by complementary pairing of its triplet of nucleotides with its codon of three nucleotides in the mRNA. A second molecule of tRNA charged with its specific amino acid, tryptophan (Try), has docked at the adjacent triplet of nucleotides and awaits the action of ribosomal enzymes to form the peptide bond with phenylalanine. Linking the amino acid to the peptide chain releases it from its tRNA and allows the empty tRNA to dissociate from the mRNA. A third molecule of tRNA, which brought the preceding molecule of leucine (Leu), is departing from the left, while a fourth molecule of tRNA, carrying its cargo of glycine (Gly), arrives from the right and waits to form the complementary bonds with the next codon in the mRNA that will bring the glycine in position to be joined to tryptophan at the carboxyl terminus of the peptide chain. The ribosome moves down the mRNA, adding one amino acid at a time until it reaches a stop codon. (Adapted from Alberts et al, Molecular biology of the cell, New York: Garland Publishing, 1994.)

During rapid protein synthesis multiple ribosomes bind to a single mRNA separated by about 80 nucleotides to form polysomes. In this way, a single molecule of mRNA is used repetitively to synthesize multiple copies of a protein.

Posttranslational Processing

Most newly translated proteins must be modified and translocated to appropriate cellular or extracellular sites before they are ready to assume their biological functions. The peptide chain that emerges from the ribosome is subjected to various steps of posttranslational processing and directed toward an appropriate cellular compartment even before its synthesis is complete. For example, the N-terminal peptide of proteins destined to be secreted or integrated into membranes passes through a specialized pore in the membrane of the endoplasmic reticulum where the proteins are folded into their proper configurations and processed. Processing may include removal of the N-terminal ''leader'' sequence that provided the signal for entering the endoplasmic reticulum, formation of disulfide bonds between cysteines on adjacent loops of the protein, proteolytic cleavage at one or more internal sites, attachment of carbohydrate or lipid moieties, and the formation of complexes with one or more products of other genes. Cleavage may release one or more biologically active proteins or peptides from a single precursor protein (see Fig. 6). Cleavage may also produce separate noncovalently attached subunits of a protein complex. Instructions for posttranslational processing and targeting to precise cellular loci are encoded in short sequences of amino acids within the protein itself. Mutations in these critical areas therefore can have profound effects on the stability or functionality of a protein even when amino acid sequences in catalytic or regulatory domains are unchanged. Similarly, how a protein folds or coils to assume its final shape is determined largely by its amino acid sequence, but proper folding is sometimes assisted by interaction with other proteins called chaperones.

From the foregoing, it is apparent that expression of the final product of any gene is controlled at multiple steps. The most thoroughly studied, and perhaps most

FIGURE 6 Examples of posttranslational processing. The straight chain primary translation product (A) folds into its proper conformation (B), either spontaneously or with the aid of cellular proteins called chaperons. Cysteines brought into alignment in the folded protein can now be oxidized to form disulfide bridges (C). Proteolytic clipping by processing proteases cleave peptide bonds (D), and one or more chains of carbohydrate is added (E).

FIGURE 6 Examples of posttranslational processing. The straight chain primary translation product (A) folds into its proper conformation (B), either spontaneously or with the aid of cellular proteins called chaperons. Cysteines brought into alignment in the folded protein can now be oxidized to form disulfide bridges (C). Proteolytic clipping by processing proteases cleave peptide bonds (D), and one or more chains of carbohydrate is added (E).

important, of these regulated steps is the initiation of gene transcription, when the assembly of a complex array of regulatory factors provides a variety of opportunities for cell-specific and temporally dependent fine tuning. This is the principle site of regulation of gene expression by extracellular agents. After transcription, both the splicing process to form the mRNA and the stability of the mRNA are also subject to regulation, as is the process of mRNA transport out of the nucleus. Splicing may be cell specific, so that the same RNA transcript of a gene may give rise to different mRNAs in different cells. The complex reactions associated with the initiation of protein synthesis are also subject to control. Enzymatic processing of the translation product may determine whether or not an active protein or multiple proteins are formed and targeted to appropriate cellular loci. Proteolytic cleavage in different cell types can form different protein products from the same precursor depending on the availability and activity of processing enzymes of different specificities. In fact, as a result of alternate splicing of RNA and the complexities of posttranslational processing, it has been estimated that the 30 to 35,000 pairs of genes in the human genome may give rise to as many as 2,000,000 proteins.

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