Artificial transmembrane oncoproteins smaller than the bovine papillomavirus E5 protein redefine sequence requirements for activation of the platelet-derived growth factor beta receptor.
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) beta receptor and induces ligand-independent receptor activation. Three specific features of BPV E5 are considered important for its ability to activate the PDGF beta 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 beta 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 beta 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.
Talbert-Slagle
Kristina
K
Department of Genetics, P.O. Box 208034, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Marlatt
Sara
S
Barrera
Francisco N
FN
Khurana
Ekta
E
Oates
Joanne
J
Gerstein
Mark
M
Engelman
Donald M
DM
Dixon
Ann M
AM
Dimaio
Daniel
D
D000595:Amino Acid Sequence; D000818:Animals; D002471:Cell Transformation, Neoplastic; D019281:Dimerization; D005347:Fibroblasts / Q000821:virology; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000737:chemistry*; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D007377:Interleukin-3; D015513:Oncogene Proteins; D009856:Oncogene Proteins, Viral; C054304:oncogene protein E5, Bovine papillomavirus type 1; D020797:Receptor, Platelet-Derived Growth Factor beta