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Proc Natl Acad Sci U S A. 2017 Aug 29;114(35):E7262-E7271. doi: 10.1073/pnas.1705622114. Epub 2017 Aug 14.

Two transmembrane dimers of the bovine papillomavirus E5 oncoprotein clamp the PDGF β receptor in an active dimeric conformation.

Author information

1
Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520-8024.
2
Department of Genetics, Yale School of Medicine, New Haven, CT 06520-8005.
3
Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996-0800.
4
Department of Chemistry, University of California, Irvine, CA 92697-2025.
5
Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520-8024; daniel.dimaio@yale.edu donald.engelman@yale.edu.
6
Yale Cancer Center, New Haven, CT 06520-8028.
7
Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520-8040.

Abstract

The dimeric 44-residue E5 protein of bovine papillomavirus is the smallest known naturally occurring oncoprotein. This transmembrane protein binds to the transmembrane domain (TMD) of the platelet-derived growth factor β receptor (PDGFβR), causing dimerization and activation of the receptor. Here, we use Rosetta membrane modeling and all-atom molecular dynamics simulations in a membrane environment to develop a chemically detailed model of the E5 protein/PDGFβR complex. In this model, an active dimer of the PDGFβR TMD is sandwiched between two dimers of the E5 protein. Biochemical experiments showed that the major PDGFβR TMD complex in mouse cells contains two E5 dimers and that binding the PDGFβR TMD to the E5 protein is necessary and sufficient to recruit both E5 dimers into the complex. These results demonstrate how E5 binding induces receptor dimerization and define a molecular mechanism of receptor activation based on specific interactions between TMDs.

KEYWORDS:

BPV; blue native gel electrophoresis; oncogene; transmembrane protein complex; traptamer

PMID:
28808001
PMCID:
PMC5584431
DOI:
10.1073/pnas.1705622114
[Indexed for MEDLINE]
Free PMC Article

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