Signal peptide-binding drug as a selective inhibitor of co-translational protein translocation.

Abstract

Author SummaryAll cells are highly crowded with proteins that, once synthesized, have to reach their proper subcellular location in order to maintain the cellular homeostasis. Approximately 30% of the proteome needs to be sorted from the cytosol and inserted into, or transported through, biological membranes. For proteins sorted via the secretory pathway, an important step is the translocation into a cellular compartment called the endoplasmic reticulum (ER). The cell uses an elegant way to discriminate proteins that need to be translocated into the ER from those that have to reside in the cytosol by scanning for the presence of an N-terminal ER-entry tag. Although these tags, called signal peptides, have a common structure, they each contain a unique hydrophobic peptide sequence. In this work, we describe how a small chemical drug, CADA, can bind to one specific signal peptide present in the human CD4 pre-protein. We show that by influencing the signal peptide orientation in the translocation channel located in the ER membrane, CADA prevents CD4 translocation into the ER lumen. As a consequence, the CD4 protein is not properly synthesized and routed to the cell surface, resulting in a clear reduction in the amount of surface CD4, a membrane protein found on immune cells, and implicated in HIV-infection and other diseases. We believe that other drugs can be designed to selectively regulate, in a similar way, ER translocation of specific target proteins.