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Journal of Biochemistry Advance Access published online on August 30, 2007

Journal of Biochemistry, doi:10.1093/jb/mvm156
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© 2007 The Japanese Biochemical Society

SerpinB6 is an inhibitor of kallikrein-8 in keratinocytes.

Fiona L. Scott1,3,*, Jiuru Sun1, James C. Whisstock 1, Keiko Kato2 and Phillip I. Bird 1

1 Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Victoria, 3800, Australia
2Division of Structural Cell Biology, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara, 630-0101 Japan.

*CORRESPONDING AUTHOR: Dr Fiona Scott, Program in Apoptosis and Cell Death Research, Burnham Institute for Medical Research, La Jolla, CA, 92037, USA, Ph: +1 858 646 3100 x3667, Fax: +1 858 646 3199, E-mail: fscott{at}burnham.org

Received March 7, 2007; Accepted June 21, 2007


   Abstract

SerpinB6 (Proteinase inhibitor 6/PI-6) is an intracellular serpin produced by leukocytes, platelets, endothelial cells, keratinocytes and other epithelial cells. It is a potent cathepsin G inhibitor thought to protect monocytes, neutrophils and bystander cells from ectopic cathepsin G during inflammation. Here we show that serpinB6 also inhibits the human serine protease kallikrein-8 (hK8) and that in human and mouse skin, serpinB6 and kallikrein-8 co-localize in differentiated keratinocytes. SerpinB6 inhibits hK8 with an association rate constant (kass) of 1.8 ± 0.2 x 105 M-1s-1 compared to 3.4 ± 0.2 x 106 M-1s-1 for the interaction between the mouse orthologue of serpinB6 (SPI3/serpinb6a) and mouse kallikrein-8 (mK8). Molecular modeling suggested that the lower efficiency of the serpinB6/hK8 interaction is partly due to the bulkier P2 methionine residue of serpinB6 compared to the smaller P2 valine in SPI3. Taken together, these results suggest that serpinB6 is a physiologically relevant inhibitor of hK8 in skin. We postulate that serpinB6 protects the intracellular compartment of keratinocytes from ectopic hK8.

Key Words: serpinB6, SPI3, neuropsin, kallikrein, keratinocyte


3 current address: Program for Apoptosis and Cell Death Research, Burnham Institute for Medical Research, 10901 North Torrey Pines Rd, La Jolla, California, 92037, USA


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