Crystal Structure and Biochemical Characterization of Human Kallikrein 6 Reveals That a Trypsin-like Kallikrein Is Expressed in the Central Nervous System

The human kallikreins are a large multigene family of closely related serine-type proteases. In this regard, they are similar to the multigene kallikrein families characterized in mice and rats. There is a much more extensive body of knowledge regarding the function of mouse and rat kallikreins in c...

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Published in:The Journal of biological chemistry 2002-07, Vol.277 (27), p.24562-24570
Main Authors: Bernett, Matthew J., Blaber, Sachiko I., Scarisbrick, Isobel A., Dhanarajan, Pushparani, Thompson, Steven M., Blaber, Michael
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Central Nervous System - enzymology
Consensus Sequence
Humans
kallikrein 6
Kallikreins - chemistry
Kallikreins - genetics
Kallikreins - metabolism
Mice
Models, Molecular
Molecular Sequence Data
myelencephalon-specific serine proteinase
Protein Conformation
Rats
Sequence Alignment
Sequence Homology, Amino Acid
Trypsin - chemistry
Trypsin - metabolism
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Summary:The human kallikreins are a large multigene family of closely related serine-type proteases. In this regard, they are similar to the multigene kallikrein families characterized in mice and rats. There is a much more extensive body of knowledge regarding the function of mouse and rat kallikreins in comparison with the human kallikreins. Human kallikrein 6 has been proposed as the homologue to rat myelencephalon-specific protease, an arginine-specific degradative-type protease abundantly expressed in the central nervous system and implicated in demyelinating disease. We present the x-ray crystal structure of mature, active recombinant human kallikrein 6 at 1.75-Å resolution. This high resolution model provides the first three-dimensional view of one of the human kallikreins and one of only a few structures of serine proteases predominantly expressed in the central nervous system. Enzymatic data are presented that support the identification of human kallikrein 6 as the functional homologue of rat myelencephalon-specific protease and are corroborated by a molecular phylogenetic analysis. Furthermore, the x-ray data provide support for the characterization of human kallikrein 6 as a degradative protease with structural features more similar to trypsin than the regulatory kallikreins.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M202392200