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Nucleic Acids Research 2004 32(14):4182-4193; doi:10.1093/nar/gkh742
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Published online 6 August 2004

Nucleic Acids Research, Vol. 32 No. 14 © Oxford University Press 2004; all rights reserved

Essential structural and functional determinants within the forkhead domain of FOXC1

R. A. Saleem1, S. Banerjee-Basu3, T. C. Murphy2, A. Baxevanis3 and M. A. Walter1,2,*

1 Department of Medical Genetics and 2 Department of Ophthalmology, 832 Medical Sciences Building, University of Alberta, Edmonton, Alberta, Canada T6G 2H7, USA and 3 Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

* To whom correspondence should be addressed. Tel: +1 780 492 9805; Fax: +1 780 492 6934; Email: mwalter{at}ualberta.ca
Present address: R. A. Saleem, The Institute for Systems Biology, Seattle, WA, USA

Received as resubmission June 9, 2004; Revised and Accepted July 15, 2004

The forkhead domain (FHD)-containing developmental transcription factor FOXC1 is mutated in patients presenting with Axenfeld–Rieger malformations. In this paper, we report the introduction of positive, negative or neutral charged amino acids into critical positions within the forkhead domain of FOXC1 in an effort to better understand the essential structural and functional determinants within the FHD. We found that FOXC1 is intolerant of mutations at I87. Additionally, alterations of amino acids within {alpha}-helix 1 of the FOXC1 FHD affected both nuclear localization and transactivation. Amino acids within {alpha}-helix 3 were also found to be necessary for transactivation and can have roles in correct localization. Interestingly, changing amino acids within {alpha}-helix 3, particularly R127, resulted in altered DNA-binding specificity and granted FOXC1 the ability to bind to a novel DNA sequence. Given the limited topological variation of FHDs, due to the high conservation of residues, we anticipate that models of forkhead domain function derived from these data will be relevant to other members of the FOX family of transcription factors.


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