Abstract
Cleavable endoplasmic reticulum (ER) signal peptides (SPs) and other non-cleavable signal sequences target roughly a quarter of the human proteome to the ER. These short peptides, mostly located at the N-termini of proteins, are highly diverse. For most proteins targeted to the ER, it is the interactions between the signal sequences and the various ER targeting and translocation machineries such as the signal recognition particle (SRP), the protein-conducting channel Sec61, and the signal peptidase complex (SPC) that determine the proteins’ target location and provide translocation fidelity. In this review, we follow the signal peptide into the ER and discuss the recent insights that structural biology has provided on the governing principles of those interactions.
Highlights
The secretory pathway is a protein trafficking highway utilized by more than a quarter of the human proteome [1,2]
A complex network of cytosolic and endoplasmic reticulum (ER) membrane-resident macromolecules facilitate and assist the ER targeting and translocation. Both ER targeting and translocation/insertion critically depend on so-called signal sequences (SSs), short hydrophobic peptide stretches in the amino acid sequence of the newly synthesized proteins that are recognized by the secretory machinery as trafficking signals
Substrates that are targeted to the ER post-translationally require ATP-dependent chaperoning in the cytosol
Summary
The secretory pathway is a protein trafficking highway utilized by more than a quarter of the human proteome [1,2]. A complex network of cytosolic and ER membrane-resident macromolecules facilitate and assist the ER targeting and translocation Both ER targeting and translocation/insertion critically depend on so-called signal sequences (SSs), short hydrophobic peptide stretches in the amino acid sequence of the newly synthesized proteins that are recognized by the secretory machinery as trafficking signals. The SRP, a composite of one RNA and six protein molecules, binds ribosomes in a ‘scanning’ mode even before SPs emerge from the exit tunnel [29,35,36,37,38]. The mammalian SRP54–SS interface in the ‘cargo recognition’ state has been resolved in a recent structure of SRPs in complex with ribosomes translating a type II SAS with a 16 AA hydrophobic core [14] (Figure 3a–e).
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