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Originally published In Press as doi:10.1074/jbc.M112038200 on February 7, 2002

J. Biol. Chem., Vol. 277, Issue 16, 13455-13462, April 19, 2002
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Dissociation Time from DNA Determines Transcriptional Function in a STAT1 Linker Mutant*

Edward Yang, Melissa A. Henriksen, Olaf SchaeferDagger , Natalia Zakharova, and James E. Darnell Jr.§

From the Laboratory of Molecular Cell Biology, The Rockefeller University, New York, New York 10021-6399

The STAT1 transcription factor is organized into several highly conserved domains, each of which has been assigned a function with the exception of the linker domain. We previously characterized a mutant in the linker domain of STAT1 that gave normal DNA binding using a standard probe in an electrophoretic mobility assay but failed to activate transcription in response to interferon gamma . We now report the mechanistic basis for the inactivity of this STAT1(K544A/E545A) mutant. Rather than failing to attract transcriptional coactivators, the STAT1(K544A/E545A) mutant has a subtle biophysical defect, which prevents accumulation of the activated protein on chromatin in vivo: the mutant has comparable Kd with greatly increased koff for DNA binding. The increase in both on-rate and off-rate of DNA binding results in a substantially reduced residence time of STAT1(K544A/E545A) on STAT binding sites. We find a similar correlation between off-rate and transcriptional potency for STAT1(N460A), which bears a mutation in the DNA binding domain. These results yield insight into the rate of complex assembly involving STAT1 that leads to transcriptional stimulation.

* This work was supported by Grants AI32489 and AI34420 as well as Training Grant CA09673 (to E. Y.), all from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Present address: Zentrum Biochemie, Medizinische Hochschule Hannover, Hannover D-30623, Germany.

§ To whom correspondence should be addressed: Laboratory of Molecular Cell Biology, The Rockefeller University, 1230 York Ave., Box 235, New York, NY 10021-6399. Tel.: 212-327-8791; Fax: 212-327-8801; E-mail: darnell@mail.rockefeller.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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