Department of Cell Biology
tel: (617) 278-3140 Fax: (617) 278-3131
Our objective is to understand the molecular mechanisms governing the specificity and regulation of macro molecular traffic mediated by clathrin-coated pits and coated vesicles, a major apparatus that the cell uses to move receptors and ligands into and through the cell. These organelles undergo continual, rapid cycles of assembly and disassembly leading to the selective endocytosis of molecules such as growth factor receptors and neurotransmitters, immunoglobulins, low density lipoproteins and certain viruses; the traffic of the mannose 6-phosphate receptor; 7-transmembrane, g-coupled receptors and the secretion of insulin and ACTH.
Clathrin, the building block of the coat, organizes itself into basket-shaped lattices, providing structural stability for the vesicles, and, possibly, the driving force for internalization of segments of membranes. APs, the most prominent and ubiquitous of the proteins associated with the clathrin coat, are related heterotetrameric assemblies, whose detailed polypeptide composition depends on their intracellular location: AP-1 are complexes associated with coats at the trans-Golgi network and AP-2 are the complexes associated with coats at the plasma membrane. These APs interact with receptors, clathrin, and other membrane-associated proteins, and they appear to serve as critical regulatory junctions in coated vesicle activities.
We are currently examining the high resolution structure (by x-rays and electron microscopy) of clathrin and its partner proteins; how does clathrin interacts with its AP complexes in order to form coats; the mechanism that allows the specific and regulated association of AP-1 and AP-2 complexes with the trans-Golgi network or the plasma membrane; and how an AP complex recognizes the membrane receptor that is specifically recruited into a coated pit. With these biochemical and cell biological studies we expect to obtain a framework for analyzing some of the molecular contacts and switches that participate in the regulation, availability and intracellular traffic of the many molecules involved in signal transduction, immune response, lipid homeostasis and cell-cell recognition.
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