Primary Department Affiliation: Cell, Developmental and Integrative Biology
Research Focus: Membrane Traffic; Protein Degradation
The mechanism of protein degradation is fundamental to our understanding of membrane traffic. Its medical relevance arises from the range of human diseases caused by the failed delivery of a specific protein to its appropriate site or the premature degradation of a critical cellular component. Cystic fibrosis, for example, results from the failure of the delivery of the receptor (CTFR) to the cell surface. Certain cancers result from the rapid degradation of the Ptc (patched) receptor.
A major aim of our work is the understanding of the control of intracellular membrane traffic. We seek to understand how cells mediate the transport of crucial proteins to their correct site. In eukaryotic cells, secreted and cell surface proteins are transported from the site of synthesis in the endoplasmic reticulum (ER), through the Intermediate Compartment (IC) and the Golgi complex to the cell surface or to the endosomal/lysosomal system. We are developing a “virtual” time and space map of all of the molecular events that occur during this transport. We have cloned several proteins that are required fro transport and are using biochemical, immunological, morphological, genetic, and molecular methods to define their exact functions. A detailed understanding of protein traffic at the molecular level would enable the development of disease-specific therapies that target the deficient steps in protein transport.
The control of protein degradation is a complementary area of focus within our group. Chaperones catalyze the correct folding of newly synthesized proteins in the ER. Incorrect or inefficient folding leads to the scavenging of the protein by the ER quality control system and its elimination by proteasomal degradation. We have developed an in vivo system, using the genetically tractable yeast, Saccharomyces cerevisiae, to analyze this process. The allowed the identification of a multi-component sorting machinery in yeast that sequesters misfolded proteins in ER subdomains prior to their degradation. We are seeking to identify a similar system in mammalian cells. This project should lead to development of technology that will selectively slow the degradative sorting of clinically relevant proteins.
Current Members Of The Laboratory
Visiting Professor: Cecilia Alvarez
Post-Doctoral Fellows: Karl Fu, Melanie Styers
Current Graduate Students: Robert Grabski, Cristy Tower, Tomasz Szul, Jason Lowery