Wednesday Seminar Series

Come hear from Caltech faculty and JPL scientists about their exciting research! Lunch will be served to the first 100 guests.

This week features Rebecca Voorhees, Assistant Professor Biology; Investigator, Heritage Medical Research Institute.

Mechanism of Protein Targeting to the Endoplasmic Reticulum

Secreted and integral membrane proteins compose ~30% of the eukaryotic proteome, and are essential for a range of cellular functions including intracellular trafficking, cell signaling, and the transport of molecules across the lipid bilayer. Defects in membrane protein maturation underlie numerous protein misfolding diseases, and more than half of all therapeutic drugs bind a membrane protein target. The essential roles of these proteins, as well as the consequences of their failed maturation, underscore the importance of understanding the molecular details of membrane protein biogenesis. The majority of secreted and integral membrane proteins are co-translationally targeted to the ER by the signal recognition particle (SRP), and are then inserted into the lipid bilayer by the universally conserved translocation channel, Sec61. Accurate sorting of proteins to the ER is essential to maintaining cellular homeostasis and preventing protein mislocalization, which can lead to disease. Specificity during this process is achieved via two selection steps: the first carried out by SRP in the cytosol, and the second by Sec61 at the membrane. In order to examine the molecular basis for substrate recognition, we have used cryo-electron microscopy (cryo-EM) to visualize a series of structures that trace the path of a hydrophobic sequence from its recognition by SRP to its insertion and translocation by Sec61. Together these structures suggest a common strategy employed by both SRP and Sec61 for selective recognition of hydrophobic sequences that ensures fidelity during membrane protein targeting.