Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 26 September 2003:
Vol. 301. no. 5641, pp. 1904 - 1908
DOI: 10.1126/science.1085945
Prev | Table of Contents | Next

Reports

Reprogramming Control of an Allosteric Signaling Switch Through Modular Recombination

John E. Dueber,1,3 Brian J. Yeh,2,3 Kayam Chak,3 Wendell A. Lim3*

Many eukaryotic signaling proteins are composed of simple modular binding domains, yet they can display sophisticated behaviors such as allosteric gating and multi-input signal integration, properties essential for complex cellular circuits. To understand how such behavior can emerge from combinations of simple domains, we engineered variants of the actin regulatory protein N-WASP (neuronal Wiskott-Aldrich syndrome protein) in which the "output" domain of N-WASP was recombined with heterologous autoinhibitory "input" domains. Synthetic switch proteins were created with diverse gating behaviors in response to nonphysiological inputs. Thus, this type of modular framework can facilitate the evolution or engineering of cellular signaling circuits.

1 Program in Biological Sciences, University of California, San Francisco, CA 94143–2240, USA.
2 Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, CA 94143–2240, USA.
3 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143–2240, USA.

* To whom correspondence should be addressed. E-mail: wlim{at}itsa.ucsf.edu.

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Molecular Mechanism of the Syk Activation Switch.
E. Tsang, A. M. Giannetti, D. Shaw, M. Dinh, J. K. Y. Tse, S. Gandhi, H. Ho, S. Wang, E. Papp, and J. M. Bradshaw (2008)
J. Biol. Chem. 283, 32650-32659
   Abstract »    Full Text »    PDF »
Light-activated DNA binding in a designed allosteric protein.
D. Strickland, K. Moffat, and T. R. Sosnick (2008)
PNAS 105, 10709-10714
   Abstract »    Full Text »    PDF »
Design of protein function leaps by directed domain interface evolution.
J. Huang, A. Koide, K. Makabe, and S. Koide (2008)
PNAS 105, 6578-6583
   Abstract »    Full Text »    PDF »
Biology by design: reduction and synthesis of cellular components and behaviour.
P. Marguet, F. Balagadde, C. Tan, and L. You (2007)
J R Soc Interface 4, 607-623
   Abstract »    Full Text »    PDF »
Neurotrophic factors switch between two signaling pathways that trigger axonal growth.
M. Paveliev, M. Lume, A. Velthut, M. Phillips, U. Arumae, and M. Saarma (2007)
J. Cell Sci. 120, 2507-2516
   Abstract »    Full Text »    PDF »
Designing biological systems.
D. A. Drubin, J. C. Way, and P. A. Silver (2007)
Genes & Dev. 21, 242-254
   Abstract »    Full Text »    PDF »
Synthetic biology--putting engineering into biology.
M. Heinemann and S. Panke (2006)
Bioinformatics 22, 2790-2799
   Abstract »    Full Text »    PDF »
Protein-tyrosine Kinase and GTPase Signals Cooperate to Phosphorylate and Activate Wiskott-Aldrich Syndrome Protein (WASP)/Neuronal WASP.
E. Torres and M. K. Rosen (2006)
J. Biol. Chem. 281, 3513-3520
   Abstract »    Full Text »    PDF »
Activation of the Src Family Kinase Hck without SH3-Linker Release.
E. C. Lerner, R. P. Trible, A. P. Schiavone, J. M. Hochrein, J. R. Engen, and T. E. Smithgall (2005)
J. Biol. Chem. 280, 40832-40837
   Abstract »    Full Text »    PDF »
Rational Design of p53, an Intrinsically Unstructured Protein, for the Fabrication of Novel Molecular Sensors.
M. L. Geddie, T. L. O'Loughlin, K. K. Woods, and I. Matsumura (2005)
J. Biol. Chem. 280, 35641-35646
   Abstract »    Full Text »    PDF »
Directed evolution of protein switches and their application to the creation of ligand-binding proteins.
G. Guntas, T. J. Mansell, J. R. Kim, and M. Ostermeier (2005)
PNAS 102, 11224-11229
   Abstract »    Full Text »    PDF »
Two Distinct Head-Tail Interfaces Cooperate to Suppress Activation of Vinculin by Talin.
D. M. Cohen, H. Chen, R. P. Johnson, B. Choudhury, and S. W. Craig (2005)
J. Biol. Chem. 280, 17109-17117
   Abstract »    Full Text »    PDF »
PDZBase: a protein-protein interaction database for PDZ-domains.
T. Beuming, L. Skrabanek, M. Y. Niv, P. Mukherjee, and H. Weinstein (2005)
Bioinformatics 21, 827-828
   Abstract »    Full Text »    PDF »
Counting of Rif1p and Rif2p on Saccharomyces cerevisiae Telomeres Regulates Telomere Length.
D. L. Levy and E. H. Blackburn (2004)
Mol. Cell. Biol. 24, 10857-10867
   Abstract »    Full Text »    PDF »
Design of a directed molecular network.
G. Ashkenasy, R. Jagasia, M. Yadav, and M. R. Ghadiri (2004)
PNAS 101, 10872-10877
   Abstract »    Full Text »    PDF »
From the Cover: Switching desaturase enzyme specificity by alternate subcellular targeting.
I. Heilmann, M. S. Pidkowich, T. Girke, and J. Shanklin (2004)
PNAS 101, 10266-10271
   Abstract »    Full Text »    PDF »
Sequence-based prediction of protein domains.
J. Liu and B. Rost (2004)
Nucleic Acids Res. 32, 3522-3530
   Abstract »    Full Text »    PDF »
Evolution and evolvability of proteins in the laboratory.
M. W. Deem (2004)
PNAS 101, 3997-3998
   Full Text »    PDF »
2003: Signaling Breakthroughs of the Year.
E. M. Adler, N. R. Gough, and L. B. Ray (2004)
Sci. STKE 2004, eg1
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)