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Journal of Virology, October 2009, p. 9773-9785, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.00946-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Artificial Transmembrane Oncoproteins Smaller than the Bovine Papillomavirus E5 Protein Redefine Sequence Requirements for Activation of the Platelet-Derived Growth Factor β Receptor{triangledown},{dagger}

Kristina Talbert-Slagle,1 Sara Marlatt,2 Francisco N. Barrera,3 Ekta Khurana,3 Joanne Oates,5 Mark Gerstein,3 Donald M. Engelman,3 Ann M. Dixon,5 and Daniel DiMaio2,3,4*

Department of Epidemiology and Public Health, P.O. Box 208034,1 Department of Genetics, P.O. Box 208005,2 Department of Molecular Biophysics & Biochemistry, P.O. Box 208114,3 Department of Therapeutic Radiology, P.O. Box 208040, Yale University School of Medicine, New Haven, Connecticut 06520,4 Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, United Kingdom5

Received 13 May 2009/ Accepted 30 June 2009

The bovine papillomavirus E5 protein (BPV E5) is a 44-amino-acid homodimeric transmembrane protein that binds directly to the transmembrane domain of the platelet-derived growth factor (PDGF) β receptor and induces ligand-independent receptor activation. Three specific features of BPV E5 are considered important for its ability to activate the PDGF β receptor and transform mouse fibroblasts: a pair of C-terminal cysteines, a transmembrane glutamine, and a juxtamembrane aspartic acid. By using a new genetic technique to screen libraries expressing artificial transmembrane proteins for activators of the PDGF β receptor, we isolated much smaller proteins, from 32 to 36 residues, that lack all three of these features yet still dimerize noncovalently, specifically activate the PDGF β receptor via its transmembrane domain, and transform cells efficiently. The primary amino acid sequence of BPV E5 is virtually unrecognizable in some of these proteins, which share as few as seven consecutive amino acids with the viral protein. Thus, small artificial proteins that bear little resemblance to a viral oncoprotein can nevertheless productively interact with the same cellular target. We speculate that similar cellular proteins may exist but have been overlooked due to their small size and hydrophobicity.

* Corresponding author. Mailing address: Department of Genetics, Yale University, P.O. Box 208005, New Haven, CT 06520-8005. Phone: (203) 785-2684. Fax: (203) 785-6765. E-mail: daniel.dimaio{at}yale.edu

{triangledown} Published ahead of print on 15 July 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, October 2009, p. 9773-9785, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.00946-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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