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PEDS Advance Access originally published online on October 22, 2007
Protein Engineering Design and Selection 2007 20(10):505-509; doi:10.1093/protein/gzm051
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Increasing the potency of a cytotoxin with an arginine graft

Stephen M. Fuchs1,3, Thomas J. Rutkoski1, Vanessa M. Kung2, Ryan T. Groeschl1 and Ronald T. Raines1,2,4

1Department of Biochemistry, University of Wisconsin–Madison, 433 Babcock Drive, Madison, WI 53706-1544, USA 2Department of Chemistry, University of Wisconsin–Madison, 1101 University Avenue, Madison, WI 53706-1322, USA 3Present address: Lineberger Comprehensive Cancer Center, The University of North Carolina–Chapel Hill, 405 MEJ Building, Chapel Hill, NC 27599, USA

4 To whom correspondence should be addressed. E-mail: raines{at}biochem.wisc.edu

Variants and homologs of bovine pancreatic ribonuclease (RNase A) can exhibit cytotoxic activity. This toxicity relies on cellular internalization of the enzyme. Residues Glu49 and Asp53 form an anionic patch on the surface of RNase A. We find that replacing these two residues with arginine does not affect catalytic activity or affinity for the cytosolic ribonuclease inhibitor (RI) protein. This ‘arginine graft’ does, however, increase toxicity towards human cancer cells. Appending a nonaarginine domain to this cationic variant results in an additional increase in cytotoxicity, providing one of the most cytotoxic known variants of RNase A. These findings correlate the potency of a ribonuclease with its deliverance of ribonucleolytic activity to the cytosol, and indicate a rational means to enhance the efficacy of ribonucleases and other cytotoxic proteins.

Keywords: cancer/Coulombic interaction/protein transduction domain/ribonuclease/ribonuclease inhibitor

Received April 14, 2007; revised August 1, 2007; accepted September 10, 2007.


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