Too long for translocation?

Abstract

Peptides that are made too quickly can't get into the ER, say Asvin Lakkaraju, Katharina Strub (University of Geneva, Switzerland), and colleagues. It seems that the peptides become too long for the translocation machinery to deal with. Figure 1 SRP (light green) targets nascent chains via the SRP receptor (blue) to the translocon (orange) for translocation into the ER. Chains that become too long before translocation are degraded. The signal sequence at the amino terminal of a growing peptide chain is required for translocating the peptide into the ER. The signal sequence binds a signal recognition particle (SRP), which in turn binds to an SRP receptor on the endoplasmic reticulum and guides the nascent chain to a translocon—a channel that feeds the new peptides into the ER. Mammalian SRP has been known to delay elongation in vitro, but the significance of the delay, and its occurrence in vivo, was unknown. To explore SRP's role in vivo, the authors prepared a mutated version of human SRP14 that specifically lacked the delaying function. SRP14's ability to bind to nascent peptides and to the SRP receptor remained intact. In cells that carried the mutant SRP, elongation sped up, but the final concentration of secreted protein dropped and growth suffered. Closer inspection revealed that translocation in these cells had slowed down and nascent peptide chains were being degraded. The effects of mutant SRP could be mitigated with antibiotics that slowed elongation. They could also be mitigated by increasing the number of SRP receptor molecules. Together, the data suggest that overly long peptides, produced as a result of faster elongation, can still bind to the SRP receptor but do so unproductively—perhaps by inhibiting the receptor's ability to engage with the translocon. Translation elongation, it appears, has the ability to go at a much faster pace than the normal cellular translocation machinery can cope with, and thus requires SRP to put the brakes on. Why elongation has evolved to be so super speedy, however, is not yet clear. Lakkaraju, A.K.K., et al. 2008. Cell. 133:440–451. [PubMed]