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Protein Science (2008), 17:664-672. Published by Cold Spring Harbor Laboratory Press. Copyright © 2008 The Protein Society
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Substrate specificity of human kallikreins 1 and 6 determined by phage display

Hai-Xin Li1,7, Bum-Yeol Hwang1,2,7, Gurunathan Laxmikanthan3, Sachiko I. Blaber3, Michael Blaber3, Pavel A. Golubkov4, Pengyu Ren4, Brent L. Iverson1,5, and George Georgiou1,2,4,6

1 Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas 78712, USA
2 Department of Chemical Engineering, University of Texas, Austin, Texas 78712, USA
3 Department of Biomedical Sciences, Florida State University, Tallahassee, Florida 32306-4300, USA
4 Department of Biomedical Engineering, University of Texas, Austin, Texas 78712, USA
5 Department of Chemistry and Biochemistry, University of Texas, Austin, Texas 78712, USA
6 Section of Molecular Genetics and Microbiology, University of Texas, Austin, Texas 78712, USA

(RECEIVED November 2, 2007; FINAL REVISION January 11, 2008; ACCEPTED January 12, 2008)

The human tissue kallikrein (KLK) family contains 15 secreted serine proteases that are expressed in a wide range of tissues and have been implicated in different physiological functions and disease states. Of these, KLK1 has been shown to be involved in the regulation of multiple physiological processes such as blood pressure, smooth muscle contraction, and vascular cell growth. KLK6 is overexpressed in breast and ovarian cancer tissues and has been shown to cleave peptide derived from human myelin protein and Aβ amyloid peptide in vitro. Here we analyzed the substrate specificity of KLK1 and KLK6, by substrate phage display using a random octapeptide library. Consistent with earlier biochemical data, KLK1 was shown to exhibit both trypsin- and chymotrypsin-like selectivities with Tyr/Arg preferred at site P1, Ser/Arg strongly preferred at P1', and Phe/Leu at P2. KLK6 displayed trypsin-like activity, with the P1 position occupied only by Arg and a strong preference for Ser in P1'. Docking simulations of consensus peptide provide information on the identity of the enzyme residues that are responsible for substrate binding. Bioinformatic analysis suggested several putative KLK6 protein substrates, such as ionotropic glutamate receptor (GluR) and synphilin.

Keywords: human kallikrein; phage display; substrate specificity; molecular modeling


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