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Nucleic Acids Research Advance Access originally published online on June 28, 2008
Nucleic Acids Research 2008 36(13):4390-4401; doi:10.1093/nar/gkn400
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Nucleic Acids Research, 2008, Vol. 36, No. 13 4390-4401
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Structural Biology

A protein functional leap: how a single mutation reverses the function of the transcription regulator TetR

Marcus Resch1, Harald Striegl1, Eva Maria Henssler2, Madhumati Sevvana1, Claudia Egerer-Sieber1, Emile Schiltz3, Wolfgang Hillen2 and Yves A. Muller1,*

1Lehrstuhl für Biotechnik, 2Lehrstuhl für Mikrobiologie, Department of Biology, Friedrich-Alexander University Erlangen-Nuremberg, Henkestrasse 91 and Staudtstrasse 5, D-91052 Erlangen and 3Institut für Organische Chemie und Biochemie, University of Freiburg, Albertstrasse 21, D-79104 Freiburg, Germany

*To whom correspondence should be addressed. Tel: +49 0 9131 85 23082; Fax: +49 0 9131 85 23080; Email: ymuller{at}biologie.uni-erlangen.de

Received March 20, 2008. Revised June 5, 2008. Accepted June 7, 2008.

Today's proteome is the result of innumerous gene duplication, mutagenesis, drift and selection processes. Whereas random mutagenesis introduces predominantly only gradual changes in protein function, a case can be made that an abrupt switch in function caused by single amino acid substitutions will not only considerably further evolution but might constitute a prerequisite for the appearance of novel functionalities for which no promiscuous protein intermediates can be envisaged. Recently, tetracycline repressor (TetR) variants were identified in which binding of tetracycline triggers the repressor to associate with and not to dissociate from the operator DNA as in wild-type TetR. We investigated the origin of this activity reversal by limited proteolysis, CD spectroscopy and X-ray crystallography. We show that the TetR mutant Leu17Gly switches its function via a disorder–order mechanism that differs completely from the allosteric mechanism of wild-type TetR. Our study emphasizes how single point mutations can engender unexpected leaps in protein function thus enabling the appearance of new functionalities in proteins without the need for promiscuous intermediates.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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