DNA replicationError rate 10–8–10–10

Transcription into mRNA10–4

Translation of mRNA10–4

Maturation

Functionalprotein

Misfoldedprotein

Selection of tRNAs by ribosomes10–3–10–5

Ribosome

+ tRNAAmino

acid

aaRS

Aminoacylation of tRNA10–3–10–4

Aggregation

When protein production in a cell goes awry, abnormal deposits can form and contribute to various diseases known collectively as amy-loidoses1. The tendency of certain proteins to aggregate can be increased by mutations in the genes that encode them, as in Huntington’s or Alzheimer’s diseases. Or aggregation can be induced by an external factor such as a prion, for example in conditions such as mad cow disease or kuru.

In a paper published on Nature’s website today, Lee et al.2 describe another pathway by which pathological cellular aggregates can form. Certain mutant mice, called ‘sticky’ mice because of the effects on their fur, also suffer from neurodegeneration caused by the death of a type of brain cell — the Purkinje cell — induced by protein aggregation. In investigat-ing the origins of this neuron death, Lee et al. unexpectedly identified a mutation in the gene coding for alanyl-tRNA synthetase (AlaRS), a component of the gene-expression machinery by which aminoacyl-transfer RNAs translate messenger RNA into an amino-acid sequence on the ribosome. Closer inspection revealed that this mutation increases the frequency of errors during translation, leading to the grad-ual accumulation of inaccurately synthesized proteins that eventually form aggregates. As well as discovering another cause of cellular protein aggregation, Lee et al. demonstrate the importance of quality control by the amino-acyl-tRNA synthetases (aaRSs), the family to which AlaRS belongs, in the intricate context of a multicellular organism.

The fidelity of information transfer is carefully controlled at each step during gene expression (Fig. 1). The most error-prone steps occur at the ribosome, where an aminoacyl-tRNA is matched with the corresponding codon (specifying an amino acid) on the mes-senger RNA, and an amino acid is paired with a tRNA by an aaRS3. With a few exceptions4, mistakes from the aminoacylation reaction cannot be corrected, which almost inevitably leads to the incorporation of the wrong amino acid during protein synthesis5. AlaRS is the aaRS that attaches the amino acid alanine (Ala) to its corresponding transfer RNA (tRNAAla) during protein synthesis.

The mutation Lee et al. identified does not impair the expression, structure or solubility of AlaRS, nor does it reduce the capacity for Ala-tRNAAla synthesis; instead, the mutated pro-tein is less able to recognize and correct its own mistakes, leading to the accidental attachment

of serine to tRNAAla. This is because the muta-tion leads to a sequence impairment in the AlaRS ‘editing site’, the domain of the protein that normally ensures that incorrectly activated amino acids are removed before they can be used for protein synthesis6. Editing by aaRSs is

MOLECULAR BIOLOGY

Sticky end in protein synthesisHervé Roy and Michael Ibba

It’s not clear what general level of accuracy is required in translating the genetic code. But the protective role of proof-reading is evident from a case in which a small mistake has a catastrophic effect.

Figure 1 | Accuracy in gene expression. Transfer of information from the DNA sequence of a gene to the corresponding amino-acid sequence of a protein requires transcription of the sequence into messenger RNA, then translation of that RNA into an amino-acid sequence at ribosomes, through the agency of amino-acid-specific transfer RNAs. These steps are all prone to error (typical rates are shown in red). The inset shows the aminoacylation of tRNA, in which an amino acid is paired with a tRNA by the enzyme aminoacyl-tRNA synthetase (aaRS). It is a failure of quality control at this stage that Lee et al.2 show causes neurodegeneration in ‘sticky mice’. Once synthesized, a protein usually becomes functional. In some cases, however, misfolding occurs. Most misfolded proteins are degraded by the cell — but some form insoluble aggregates that, as in the sticky mouse, can lead to disease.

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found in numerous systems, and serves to eliminate errors that inevitably arise when try-ing to discriminate between pairs of similar amino acids7.

In the case of AlaRS, serine is mistakenly activated and attached to tRNA at the active site with a frequency of about 1 in 500 compared with alanine. Then, rather than being released for protein synthesis, as occurs for alanine, the misactivated serine moves to the editing site where it is removed from the tRNA. It is this final step that is specifically impaired in the sticky mouse; Lee and colleagues’ in vitro analyses2 showed that, rather than hydrolysing Ser-tRNAAla, the mutated AlaRS produces more of this mischarged species, leading to errors in protein synthesis when alanine codons are mis-takenly translated as serine. The results of these mistakes, the frequency of which is unknown, are protein misfolding, accumulation of protein aggregates and progressive neurodegeneration.

Editing by aaRSs has long been assumed to be a point of quality control in translation, although evidence for this role has been sparse until now. Studies in microorganisms showed that defects in editing impaired competitive-

ness but were not usually lethal8,9, suggest-ing that cells can cope with a certain degree of error at this final step of gene expression. The work of Lee et al.2 shows just how fine the line is between a tolerable degree of error and a catastrophic loss of accuracy in protein syn-thesis. The loss in editing activity caused by the mutated AlaRS has no discernible effect on the efficiency of protein synthesis in non-neuronal cells, but has a detrimental effect on Purkinje cells. This may be because, as these cells do not divide, there is no ‘dilution’ of the misfolded proteins by cell division. One question not yet addressed is whether the sticky-mouse charac-teristics arise from elevated serine misincorpo-ration during synthesis of a particular subset of proteins in Purkinje cells, or from a general loss of fidelity in translation.

The discovery that ‘upstream’ defects in pro-tein synthesis might lead to amyloidoses could open new routes for treating these devastating diseases. For example, just as Lee et al. show that in mutant mouse cells elevated serine levels decrease viability, one can naively spec-ulate that a serine-restricted diet might limit erroneous protein synthesis to a level that

neuronal cells can tolerate. Clearly, this is an oversimplification, and much remains to be learned both about the formation of cellular protein aggregates and how failures in quality control contribute to this and perhaps other diseases. However that turns out, it is clear that the margin for error in translation is smaller than we thought. ■ Hervé Roy and Michael Ibba are in the Department of Microbiology and the Ohio State Biochemistry Program, Ohio State University, Columbus, Ohio 43210-1292, USA.e-mail: ibba.1@osu.edu

1. Merlini, G. & Bellotti, V. N. Engl. J. Med. 349, 583–596 (2003).

2. Lee, J. W. et al. Nature doi:10.1038/nature05096 (2006).3. Ibba, M. & Söll, D. Science 286, 1893–1897 (1999).4. Dale, T. & Uhlenbeck, O. C. Trends Biochem. Sci. 30,

659–665 (2005). 5. Wang, L., Xie, J. & Schultz, P. G. Annu. Rev. Biophys. Biomol.

Struct. 35, 225–249 (2006).6. Beebe, K., Ribas De Pouplana, L. & Schimmel, P. EMBO J.

22, 668–675 (2003).7. Jakubowski, H. & Goldman, E. Microbiol. Rev. 56, 412–429

(1992).8. Nangle, L. A., De Crécy-Lagard, V., Döring, V.

& Schimmel, P. J. Biol. Chem. 277, 45729–45733 (2002).9. Korencic, D. et al. Proc. Natl Acad. Sci. USA 101,

10260–10265 (2004).

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