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Papers In Press, published online ahead of print December 1, 2005
Dept. of Biophysics, Escola Paulista de Medicina, São Paulo 04044-020
Corresponding Author: juliano.biof{at}epm.br
Human kallikrein 6 (hK6) is abundantly expressed in the central nervous system (CNS) and implicated in demyelinating disease. The present study provides biochemical data about the substrate specificity and activation of hK6 by glycosaminoglycans (GAGs) and by kosmotropic salts, which followed the Hofmeister series. The screening of fluorescence resonance energy transfer (FRET) peptide families derived from Abz-KLRSSKQ-EDDnp resulted in the finding that Abz-AFRFSQ-EDDnp is the best synthetic substrate so far described for hK6 (kcat/Km= 38,667 mM-1s-1). It is noteworthy that the AFRFS sequence was found as a motif in the amino-terminal domain (ATD) of seven human ionotropic glutamate receptor subunits. We also examined the hK6 hydrolytic activity on FRET peptides derived from human myelin basic protein (MBP), precursor of the A amyloid peptide, reactive center loop of 1-antichymotrypsin, plasminogen, and maturation and inactivation cleavage sites of hK6, which were earlier described as natural substrates for hK6. The best substrates derived from MBP. The hK6 maturation cleavage site was poorly hydrolyzed, and no evidence was found to support a previously reported two-step self-activation process. Finally, we assayed FRET peptides derived from sequences that span the cleavage sites for activation of protease activated receptors PAR 1 to 4, and only the substrate with the PAR 2 sequence was hydrolyzed. These results further support the hypothesis that hK6 expressed in the CNS is involved in normal myelin turnover/demyelination processes, but is unlikely to self-activate. The present report also suggests the possible modulation of ionotropic glutamate receptors and activation of PAR 2 by hK6.
J. Biol. Chem, 10.1074/jbc.M510096200
Submitted on September 14, 2005
Revised on November 30, 2005
Accepted on December 1, 2005
Substrate specificity of human kallikrein 6: Salt and glycosaminoglycan activation effects
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