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Temperature-sensitive protein–DNA dimerizers

Hauschild, Karl E. and Metzler, Renee E. and Arndt, Hans-Dieter and Moretti, Rocco and Raffaelle, Marni and Dervan, Peter B. and Ansari, Aseem Z. (2005) Temperature-sensitive protein–DNA dimerizers. Proceedings of the National Academy of Sciences of the United States of America, 102 (14). pp. 5008-5013. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:HAUpnas05

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Abstract

Programmable DNA-binding polyamides coupled to short peptides have led to the creation of synthetic artificial transcription factors. A hairpin polyamide-YPWM tetrapeptide conjugate facilitates the binding of a natural transcription factor Exd to an adjacent DNA site. Such small molecules function as protein-DNA dimerizers that stabilize complexes at composite DNA binding sites. Here we investigate the role of the linker that connects the polyamide to the peptide. We find that a substantial degree of variability in the linker length is tolerated at lower temperatures. At physiological temperatures, the longest linker tested confers a "switch"-like property on the protein-DNA dimerizer, in that it abolishes the ability of the YPWM moiety to recruit the natural transcription factor to DNA. These observations provide design principles for future artificial transcription factors that can be externally regulated and can function in concert with the cellular regulatory circuitry.


Item Type:Article
Additional Information:© 2005 by The National Academy of Sciences of the USA. Contributed by Peter B. Dervan, February 24, 2005. Published online before print March 21, 2005, 10.1073/pnas.0501289102. We thank A. Aggarwal, M. Brezinski, and J. Passner for advice and help in purification of Exd. We are grateful to T. Record, R. Landick, L. Kiessling, S. Gelman, and R. Raines for helpful discussions. This work was supported by funds from University of Wisconsin Industrial and Economic Development Research Program, the March of Dimes Foundation, and the Steenbock Award (to A.Z.A.), a National Institutes of Health Molecular Bioscience training grant (R.M.), a Peterson Fellowship (K.E.H.), the National Institutes of Health (P.B.D.), and a Deutscher Akademischer Austauschdienst postdoctoral fellowship (H.-D.A.).
Subject Keywords:DNA RECOGNITION, EXTRADENTICLE, HOX PROTEINS, POLYAMIDE, RESTRICT CONFORMATIONAL FREEDOM, ESTABLISH QUALITATIVE TRENDS, AMINO-ACID-SEQUENCE, TRANSCRIPTION FACTORS, MOLECULAR PROCESSES, QUANTITATIVE MODEL, TORSIONAL ENTROPY, BINDING, EXTRADENTICLE, HOMEODOMAIN
Record Number:CaltechAUTHORS:HAUpnas05
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:HAUpnas05
Alternative URL:http://dx.doi.org/10.1073/pnas.0501289102
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1416
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:18 Jan 2006
Last Modified:26 Dec 2012 08:44

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