Capelluto Research Group
Our current research centers on the molecular structure and biochemical functions of signaling transduction systems involved in membrane trafficking and cell signaling. Our goal is to understand how protein domains transduce cell signaling from biological membranes.
Our laboratory employs biophysical approaches including high field nuclear magnetic resonance spectroscopy, circular dichroism, computer modeling, fluorescence spectroscopy, and surface plasmon resonance spectroscopy to determine ligand binding pockets and membrane insertion of protein domains from molecular to atomic resolution.
We validate our functional and structural approaches by using normal and disease-associated cell lines. With these tools we can establish how protein-ligand interactions control the function of proteins by modulating their subcellular localization.
Ubiquitylation is a highly controlled post-translational modification of proteins, in which proteins are conjugated either with monoubiquitin or polyubiquitin chains. Ubiquitin modifications on target proteins are recognized by ubiquitin-binding domains, which are found in several effector proteins. We study the function and structure of the Toll-interacting protein (Tollip), which contains the C2 and CUE ubiquitin-binding domains and participates in the innate immune signaling pathway and endosomal protein trafficking.
The Wnt-dependent, b-catenin-independent pathway modulates cell movement and behavior. A downstream regulator of this signaling pathway is Dishevelled (Dvl), which among other multiple interactions, binds to the Frizzled receptor and the plasma membrane via phosphatidic acid (PA) in a mechanism proposed to be pH dependent. We defined the structural and functional basis of PA recognition by the Dvl2 DEP domain. We also established that PA binding by the Dvl2 DEP domain is pH-dependent and resembles the mechanism of PA deprotonation.
Platelets form a clump at the site of vascular injury to stop bleeding. One negative regulator of platelet aggregation is Disabled-2 (Dab2), a protein released to the extracellular surface upon platelet activation. Dab2 inhibits platelet aggregation by competing with fibrinogen for alphaIIb-beta3 integrin receptor binding. The inhibitory role of Dab2 depends on its recognition to sulfatides, sphingolipids found on the platelet surface, which interact with coagulation proteins, playing a major role in haemostasis.
Yejin Seo (volunteer)
Neha Reddy (Nanomedicine)
Robert Wallace (Biological Sciences)
Nhyira Annan (Neuroscience, VT-LSAMP fellow)