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Infection and Immunity, October 2005, p. 6332-6339, Vol. 73, No. 10
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.10.6332-6339.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Conserved Structure and Function in the Granulysin and NK-Lysin Peptide Family

Charlotte M. A. Linde,^1* Susanna Grundström,² Erik Nordling,³ Essam Refai,³ Patrick J. Brennan,⁴ and Mats Andersson¹

Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden,¹ Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden,² Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden,³ Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado⁴

Received 29 April 2005/ Returned for modification 31 May 2005/ Accepted 23 June 2005

Granulysin and NK-lysin are homologous bactericidal proteins with a moderate residue identity (35%), both of which have antimycobacterial activity. Short loop peptides derived from the antimycobacterial domains of granulysin, NK-lysin, and a putative chicken NK-lysin were examined and shown to have comparable antimycobacterial but variable Escherichia coli activities. The known structure of the NK-lysin loop peptide was used to predict the structure of the equivalent peptides of granulysin and chicken NK-lysin by homology modeling. The last two adopted a secondary structure almost identical to that of NK-lysin. All three peptides form very similar three-dimensional (3-D) architectures in which the important basic residues assume the same positions in space. The basic residues in granulysin are arginine, while those in NK-lysin and chicken NK-lysin are a mixture of arginine and lysine. We altered the ratio of arginine to lysine in the granulysin fragment to examine the importance of basic residues for antimycobacterial activity. The alteration of the amino acids reduced the activity against E. coli to a larger extent than that against Mycobacterium smegmatis. In granulysin, the arginines in the loop structure are not crucial for antimycobacterial activity but are important for cytotoxicity. We suggest that the antibacterial domains of the related proteins granulysin, NK-lysin, and chicken NK-lysin have conserved their 3-D structure and their function against mycobacteria.

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* Corresponding author. Mailing address: Microbiology and Tumor Biology Center, Karolinska Institutet, S-171 77 Stockholm, Sweden. Phone: 46 8 524 87 113. Fax: 46 8 34 26 51. E-mail: charlotte.linde{at}mtc.ki.se.

Editor: J. D. Clements

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Infection and Immunity, October 2005, p. 6332-6339, Vol. 73, No. 10
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.10.6332-6339.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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