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Lim, Wendell
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| Research Statement | | The Molecular Logic of Cellular Signaling Systems
Signal transduction
Protein-protein recognition
Protein switches and networks
Signaling protein and network evolution
Systems biology
Biological computation
Synthetic biology
Livings cells process vast amounts of environmental information to generate sophisticated responses such as movement, growth, and differentiation. Such decisions are made by complex networks of signal transduction proteins. One of the most challenging problems in modern biology is understanding how these networks of proteins act to carry out these remarkable behaviors.
A striking commonality among eukaryotic signaling molecules is that they are composed of modular domains. Some domains carry our catalytic functions, but most mediate specific protein-protein interactions. This modular organization of signaling proteins suggests that a common toolkit of components has been used in a combinatorial fashion to evolve the complex signaling proteins and pathways we see today.
We are therefore interested in understanding the logic by which simple protein components can be used to build complex information processing systems. We would like to answer this question at several hierarchical levels:
1. How do isolated protein interaction modules function?
2. How have modular domains been combined through evolution to build signaling switches and devices, capable of complex behavior such as high specificity communication, signal integration, and feedback control?
3. How are individual signaling proteins linked into networks that display complex and highly specific systems input/output behaviors?
4. Can we engineer synthetic signaling pathways that rewire and systematically alter cellular behavior?
We are probing these questions by studying kinase and GTPase pathways involved in controlling cell movement and stress responses in yeast and mammalian cells. To achieve these goals we take a highly interdisciplinary approach that incorporates diverse techniques including:
Mechanistic biochemistry
Biophysical methods
X-ray crystallography, NMR
Molecular biology
Cell biology
Yeast genetics
Protein, pathway engineering |
Publications | | Optimization of specificity in a cellular protein interaction network by negative selection. Ali Zarrinpar, Sang-Hyun Park, and Wendell A. Lim
Nature 426, 676-680 (2003)
Reprogramming Control of an Allosteric Signaling Switch Through Modular Recombination. John E. Dueber, Brian J. Yeh, Kayam Chak, and Wendell A. Lim
Science 301, 1904-1908 (2003)
The Structure and Function of Proline Recognition Domains. Ali Zarrinpar, Roby P. Bhattacharyya, and Wendell A. Lim
Science STKE 2003, re8 (2003)
Role of Electrostatic Interactions in PDZ Domain Ligand Recognition
Baruch Z. Harris, Francis W. Lau, Naoaki Fujii, R. Kiplin Guy, and Wendell A. Lim
Biochemistry 42, 2797-2805 (2003)
Rewiring MAP Kinase Pathways Using Alternative Scaffold Assembly Mechanisms. Sang-Hyun Park, Ali Zarrinpar, and Wendell A. Lim |
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