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Department of Anatomy and Physiology
University of Dundee
Dundee DD1 5EH
Peptide-chain elongation is the programmed assembly of amino acids into a polypeptide as dictated by the sequence of bases in the mRNA. In all organisms it requires ancillary proteins termed elongation factors (see Chapter 3). These factors fall into two groups: (1) those required for the recruitment of aminoacyl-tRNAs to the ribosome and (2) those involved in the subsequent translocation event in which the ribosome moves along the mRNA. The proteins mediating these steps in the cytoplasm of eukaryotic cells are termed eEF1A1and eEF2, respectively (Table 1). Both are GTP-binding proteins and the GTP is hydrolyzed during the events associated with the function of these proteins. Each protein thus ends up bound to GDP, in which state it is inactive and must be recycled to its GTP-bound form. For eEF2 this appears to occur spontaneously (due to rapid dissociation of the GDP), whereas for eEF1A/EF-Tu a gua- nine nucleotide-exchange factor (GEF) termed eEF1B is needed. Mammalian eEF1B consists of three subunits (\u03b1\u2013\u03b3), two of which (\u03b1 and
It is the regulation of these proteins, primarily the higher eukaryotic factors, with which this chapter is concerned. The structural organization of eEF1A, eEF1B, and eEF2 is summarized in Figure 1, which also indi- cates the location of known sites of phosphorylation in these proteins.
tent, e.g., with the initiation factors elF2 and elF2B, they have been redefined as a GTP- and amino acyl-tRNA binding factor (eEF1A, formerly termed eEF1\u03b1) and a trimeric guanine nucleotide- exchange factor (eEF1B, with subunits\u03b1-\u03b3, formerly called eEF1\u03b2\u03b3\u03b4).
Altering the rate of elongation will alter the rate at which peptide chains are completed and thus is expected to contribute to the overall regulation of protein synthesis, e.g., to its activation by stimuli such as insulin (see below). Under conditions where the cell needs to conserve energy or divert it into other processes, inhibition of elongation would serve tem- porarily to reduce the amount of energy being consumed by protein syn- thesis, thus allowing, e.g., nucleoside triphosphates to be utilized for other processes (e.g., muscle contraction, see below). Regulating elongation under such circumstances can be viewed as preferable to affecting initia- tion, which is generally regarded as the major locus for control of trans- lation: Inhibiting elongation will not cause disaggregation of polysomes, thus allowing the effect to be reversed quickly, and would be unlikely to have differential effects on the translation of different mRNAs, whicha re likely to arise if initiation were inhibited.
(Chambers et al.
1998; Kahns et al.
tion. The activity of elongation factors modulates the accuracy of the process; decreased activity of eEF1A (or eEF1B), for example, results in increased fidelity (see, e.g., Carr-Schmid et al. 1999 and references there- in). Thus, it may be important to match elongation factor activity closely to the actual requirements of the cell instead of allowing a high basal activity of elongation, which might compromise translational accuracy and potentially lead to increased missense errors as well as to termination readthrough. Thus, where protein synthesis is activated, for example, it would be important to increase translation factor activity to avoid the pos- sibility that the rate of elongation would limit overall protein synthesis. Conversely, when translation initiation is inhibited, it may be important to slow the rate of elongation, thus helping to maintain polysome integrity. This could help protect mRNAs against degradation and/or allow active translation to resume quickly once initiation was switched on again.
the eukaryotic elongation factors eEF1A, eEF1B, and eEF2. To the right of each is indicat- ed the number of residues in the mammalian proteins. The stippled regions in eEF1A and eEF2 show their GTP-binding domains, and for eEF1B\u03b1 and\u03b2 the cross-hatched areas indi- cate their guanine nucleotide-exchange factor (GEF) domains. Information above or below the box indicates phosphorylation sites, using the single-letter code for amino acids. In the case of eEF2, the site of ADP-ribosylation at diphthamide (a modified form of His-714) is also indicated. The kinase(s) responsible are indicated by abbreviations as follows: (cdc2) p34cdc2; (CK-2) casein kinase-2; (eEF2k) eEF2 kinase; (PKC\u03b4) protein kinase C\u03b4. The fig- ure is not intended to imply that these phosphorylation events occur in all species: Unless otherwise indicated, the information was obtained in studies on the mammalian factors. See the text for further information. *Phosphorylation site in Asteria salina factor.
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