William Weis
Research Interests
- Several distinct intercellular junctions connect epithelial cells. Two of these, the adherens junction and the desmosome, contain cadherin cell adhesion molecules. The extracellular regions of these transmembrane proteins mediate intercellular binding, while their cytoplasmic domains are linked to the actin- (adherens junction) or intermediate filament- (desmosome) based cytoskeletons. In this way the cytoskeletons of cells comprising a tissue are linked, imparting particular morphologies and mechanical strength to the tissue. The dynamics of these complex assemblies underlie changes in cell and tissue architecture that occur during development and in many cancers. Our research aims to understand the 3-dimensional architecture and dynamics of these junctions.
Wnt signaling- The Wnt signaling pathway controls cell fate determination during embryogenesis and in the normal renewal of tissues in the adult. beta-catenin is the central component of this pathway, where it serves as a transcriptional coactivator. In the absence of a secreted Wnt protein, non-junctional beta-catenin is bound in a multiprotein “destruction complex”. Formation of this complex promotes phosphorylation of beta-catenin, which targets it for degradation by the ubiquitin/proteosome pathway. Binding of a Wnt to cell surface receptors prevents phosphorylation of beta-catenin. The resulting stabilized beta-catenin enters the nucleus and activates transcription of Wnt target genes through its interactions with Tcf-family transcription factors, proteins that contain a beta-catenin-binding domain and a sequence-specific DNA-binding domain.
We are trying to understand the mechanisms by which formation of the destruction complex enhances the phosphorylation of ?-catenin, and how beta-catenin serves as a scaffold to link the sequence-specific Tcfs to components of the general transcription machinery. We are attempting to biochemically reconstitute these complexes for mechanistic and structural studies.
Intracellular vesicle trafficking- The directed movement of membranous vesicles is essential for maintaining the compartmentalized structure of the eukaryotic cell. The machinery responsible for this process is highly conserved amongst different intracellular trafficking pathways and amongst eukaryotes. An important example is the delivery of vesicles to particular regions of the plasma membrane, which is essential for maintaining the structure of polarized cells. We are studying proteins involved in the regulated movement, docking, and fusion of vesicles with their target membranes.
Carbohydrate-based adhesion- We study specificity and mechanism in the C-type animal lectins, a large family of Ca2+-depdendent carbohydrate binding proteins. Our studies are focused on two members of this family involved in the innate and adaptive immune response.
1. DC-SIGN is a C-type lectin found on the surface of dendritic cells that is thought to mediate the binding of dendritic cells to T cells in secondary lymphoid organs. It also has a well-documented role as a receptor for HIV. It is thought that high-mannose oligosaccharides present on the HIV surface protein gp120 bind to DC-SIGN present on the surface of dendritic cells resident in mucosal tissues at sites of HIV exposure, and transit with the dendritic cells to the secondary lymphoid organs, where it is delivered to CD4+ T cells.
2. Mannose-binding proteins (MBPs) are serum proteins that recognize carbohydrate structures present on pathogens, and trigger killing of these organisms via the complement pathway. MBPs circulate as a complex with MBP-associated serine proteases (MASPs). Upon binding to a cell surface, the inactive MASP zymogen is activated, which then triggers downstream components of the complement cascade. Our studies aim to understand how binding to a target surface results in conformational rearrangements required for zymogen activation. - The Wnt signaling pathway controls cell fate determination during embryogenesis and in the normal renewal of tissues in the adult. beta-catenin is the central component of this pathway, where it serves as a transcriptional coactivator. In the absence of a secreted Wnt protein, non-junctional beta-catenin is bound in a multiprotein “destruction complex”. Formation of this complex promotes phosphorylation of beta-catenin, which targets it for degradation by the ubiquitin/proteosome pathway. Binding of a Wnt to cell surface receptors prevents phosphorylation of beta-catenin. The resulting stabilized beta-catenin enters the nucleus and activates transcription of Wnt target genes through its interactions with Tcf-family transcription factors, proteins that contain a beta-catenin-binding domain and a sequence-specific DNA-binding domain.
Cadherin-based adhesion
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