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Biochemistry. 2013 Sep 17;52(37):6304-12. doi: 10.1021/bi400619m. Epub 2013 Aug 30.

Contribution of electrostatics to the binding of pancreatic-type ribonucleases to membranes.

Author information

1
Medical Scientist Training Program and Graduate Program in Biophysics, ‡Department of Biochemistry, and §Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.

Abstract

Pancreatic-type ribonucleases show clinical promise as chemotherapeutic agents but are limited in efficacy by the inefficiency of their uptake by human cells. Cellular uptake can be increased by the addition of positive charges to the surface of ribonucleases, either by site-directed mutagenesis or by chemical modification. This observation has led to the hypothesis that ribonuclease uptake by cells depends on electrostatics. Here, we use a combination of experimental and computational methods to ascertain the contribution of electrostatics to the cellular uptake of ribonucleases. We focus on three homologous ribonucleases: Onconase (frog), ribonuclease A (cow), and ribonuclease 1 (human). Our results support the hypothesis that electrostatics are necessary for the cellular uptake of Onconase. In contrast, specific interactions with cell-surface components likely contribute more to the cellular uptake of ribonuclease A and ribonuclease 1 than do electrostatics. These findings provide insight for the design of new cytotoxic ribonucleases.

PMID:
23947917
PMCID:
PMC3839965
DOI:
10.1021/bi400619m
[Indexed for MEDLINE]
Free PMC Article

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