The Role of the Signal Peptidase Complex on the Recognition of Translocating Polypeptides

Abstract

The Sec61 translocon accommodates ER-targeted polypeptides including membrane proteins and secretory proteins in its pore for their ER translocation. Most membrane proteins are targeted to the endoplasmic reticulum (ER) by the first hydrophobic transmembrane (TM) segment whereas secretory proteins have an N-terminal signal sequence for ER targeting. TM domains and signal sequences share similar sequence context, target the whole polypeptide to the ER, and locate near to the lateral gate of the Sec translocon during translocation. The conventional view on the translocation event has not distinguished these two different types of sequences in much detail. One of the most distinctive features of signal sequences is that they are removed upon ER entry, recognized and cleaved by the signal peptidase complex (SPC). Nevertheless, Cleavage site in the C-terminus of signal sequences are of broad range and loose requisite in amino acid sequences. The SPC needs to distinguish a cleavable N-terminal signal sequence from a signal anchor sequence, the underlying mechanism of which is unknown. This study aims to elucidate the key players involved in the recognition and categorization of ER-targeted polypeptides. We recently observed that model membrane proteins with a putative SPC-mediated cleavage site were more efficiently cleaved in the absence of Spc1p or Spc2p, the non-essential subunits of the SPC. Based on the assumption that translocating nascent chains must be either recognized for or discriminated from being subjected to the SPC cleavage activity, these data suggest that Spc1p/Spc2p may be involved in the regulation of the recognition of the substrates for proper processing by the SPC. Further, deletion of Spc2p resulted in fluctuation in the translocation of ER-targeted proteins, newly suggesting its role on protein translocation.