Tom Wandless
Academic Appointments
- Associate Professor, Chemical and Systems Biology
- Member, Bio-X
- Associate Professor (By courtesy), Natural Sciences Cluster - Chemistry Department
Key Documents
Contact Information
- Academic Offices
Personal Information EmailAlternate Contact Tom Wandless Email Tel Work 650-723-4005
Professional Overview
Professional Education
| Ph.D.: | Harvard University, Chemistry (1993) |
| B.S.: | Trinity University, Biochemistry (1988) |
Graduate & Fellowship Program Affiliations
Internet Links
Scientific Focus
Current Research Interests
See http://wandless.stanford.edu/research.html for a full description.
Overview - We employ an interdisciplinary approach to studies of biological systems, combining a bit of synthetic chemistry with biochemistry, cell biology, and structural biology. More specifically, the lab concentrates on the invention of molecules and techniques that enable better studies of biological processes. In short, we invent tools for biology and we are motivated by approaches that enable new experiments with unprecedented control. These new techniques may also provide a window into mechanisms involved in maintaining cellular homeostasis. Protein quality control is a particular interest at present.
New Approaches for Conditional Control of Protein Function - We recently developed a new experimental system in which the stability of a specific protein depends on the presence or absence of a cell-permeable molecule. We started with a well-studied protein-ligand pair: the FKBP12 protein and a high-affinity, synthetic ligand called Shield-1. We screened a library of FKBP sequences to identify mutants that are unstable in the absence of Shield-1. Additional screening enriched for fusion proteins that are stabilized by Shield-1, and further characterization of these mutants revealed that the most destabilizing mutants caused a 50-fold to 100-fold reduction in the expression levels of the proteins to which they were fused. The system works in cultured mammalian cells and in living mice. Banaszynski et al (Cell 2006 and Nature Medicine 2008) describe the system in detail. Building on these early successes, we have expanded this technology is several useful ways. First, we have engineered additional DD systems using orthogonal protein- ligand combinations. Second, we have engineered a DD system that functions in the opposite sense. The fusion protein is stable in the absence of the ligand, and administration of the ligand causes the fusion protein to be rapidly degraded. Third, we have engineered an experimental system that works in yeast.
Protein Quality Control in Mammalian Cells - The DDs can be thought of as model substrates that have the potential to bridge our understanding of the physical basis of protein stability in vitro with intracellular stability. The ability to conditionally regulate the structures of these domains using high-affinity ligands allows us to quantitatively correlate specific biophysical properties with biological stability. There are two main questions that we would like to understand in this area. First, we focus on the DD proteins themselves. What property or properties of these DDs leads them to be recognized and degraded by the cellular quality control machinery? Second, we would like to have a more complete picture of the proteins that are involved in these quality control surveillance pathways. Efforts to address both of these questions are currently underway.
Protein-Protein Interactions & Bifunctional Molecules - One of the interests of the Wandless lab has been the study of synthetic molecules that are capable of binding to two different proteins. These molecules are typically comprised of two ligands for their respective proteins, and the ligands are linked by a covalent tether. In cases where the tether between the ligands is relatively long, both proteins can simultaneously bind to the bifunctional molecule to form a trimeric complex. The formation of a trimeric complex creates an environment wherein interactions between the two proteins are possible. These nascent protein-protein interactions may contribute either favorably or unfavorably to the overall stability of the ternary complex, and we have shown that these protein-protein interactions may endow the bifunctional molecules with biophysical and biological properties that are significantly different from the monomeric ligands that comprise them.
Publications
- Visualizing cellular interactions with a generalized proximity reporter. Proc Natl Acad Sci U S A. 2013
- Destabilizing domains derived from the human estrogen receptor. J Am Chem Soc. 2012; (9): 3942-5
- Differential trafficking of transport vesicles contributes to the localization of dendritic proteins. Cell Rep. 2012; (1): 89-100
- Small-molecule displacement of a cryptic degron causes conditional protein degradation. Nat Chem Biol. 2011; (8): 531-7
- A plant-like kinase in Plasmodium falciparum regulates parasite egress from erythrocytes. Science. 2010; (5980): 910-2
- Imaging the impact of chemically inducible proteins on cellular dynamics in vivo. PLoS One. 2012; (1): e30177
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