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Proc Natl Acad Sci U S A. 2015 Aug 25;112(34):E4717-25. doi: 10.1073/pnas.1514230112. Epub 2015 Aug 10.

Biologically active LIL proteins built with minimal chemical diversity.

Author information

1
Department of Genetics, Yale School of Medicine, New Haven, CT 06520-8005;
2
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520-8011;
3
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8024;
4
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8024; Yale Cancer Center, New Haven, CT 06520-8028; daniel.dimaio@yale.edu donald.engelman@yale.edu.
5
Department of Genetics, Yale School of Medicine, New Haven, CT 06520-8005; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8024; Yale Cancer Center, New Haven, CT 06520-8028; Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520-8040 daniel.dimaio@yale.edu donald.engelman@yale.edu.

Abstract

We have constructed 26-amino acid transmembrane proteins that specifically transform cells but consist of only two different amino acids. Most proteins are long polymers of amino acids with 20 or more chemically distinct side-chains. The artificial transmembrane proteins reported here are the simplest known proteins with specific biological activity, consisting solely of an initiating methionine followed by specific sequences of leucines and isoleucines, two hydrophobic amino acids that differ only by the position of a methyl group. We designate these proteins containing leucine (L) and isoleucine (I) as LIL proteins. These proteins functionally interact with the transmembrane domain of the platelet-derived growth factor β-receptor and specifically activate the receptor to transform cells. Complete mutagenesis of these proteins identified individual amino acids required for activity, and a protein consisting solely of leucines, except for a single isoleucine at a particular position, transformed cells. These surprisingly simple proteins define the minimal chemical diversity sufficient to construct proteins with specific biological activity and change our view of what can constitute an active protein in a cellular context.

KEYWORDS:

E5 protein; PDGF receptor; oncogene; synthetic biology; traptamer

PMID:
26261320
PMCID:
PMC4553812
DOI:
10.1073/pnas.1514230112
[Indexed for MEDLINE]
Free PMC Article

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