Areas of Interest
Broadly, the Baldridge lab studies protein quality control systems within the secretory pathway using Saccharomyces cerevisiae as a model. Nearly one-third of proteins are first translocated into the endoplasmic reticulum (ER) where they undergo folding events to reach their final conformations. Protein quality control systems such as ER-associated degradation (ERAD) exist to detect and remove proteins which misfold during this process. All ERAD substrates must be moved from the ER to the cytosol, where they are accessible to the ubiquitin-proteasome system for subsequent degradation. Integral membrane substrates (ERAD-M) present a unique challenge to the ERAD machinery, as their transmembrane domains (TMDs) must be disassembled and removed from the phospholipid bilayer during an energetically unfavorable process known as “extraction.” How these substrates are removed from the ER membrane during extraction is not known. Previous work has implicated the rhomboid pseudoprotease, Dfm1, but its direct role remains untested. Other rhomboid family members have been shown to participate in local lipid bilayer distortion. Thus, one attractive hypothesis is that Dfm1 mediates substrate extraction by utilizing its rhomboid motifs to destabilize substrate TMDs within the membrane and reducing the energetic barrier required for their extraction. My current project applies genetic and biochemical approaches to test this hypothesis and dissect the specific role of Dfm1 in ERAD-M.