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| The EMBO Journal
(1999) 18, 6880–6889, doi:10.1093/emboj/18.24.6880 |
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| Crystal structure of calpain reveals the structural basis for Ca2+-dependent protease activity and a novel mode of enzyme activation |
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| Christopher M. Hosfield, John S. Elce, Peter L. Davies and Zongchao Jia |
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Department of Biochemistry, Queen's University and The Protein Engineering Network of Centres of Excellence, Kingston, Ontario, Canada K7L 3N6 To whom correspondence should be addressed Zongchao Jia, jia@crystal.biochem.queensu.ca Received 20 September 1999; Revised 27 October 1999; Accepted 27 October 1999. |
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| Abstract |
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The combination of thiol protease activity and calmodulin-like EF-hands is a feature unique to the calpains. The regulatory mechanisms governing calpain activity are complex, and the nature of the Ca2+-induced switch between inactive and active forms has remained elusive in the absence of structural information. We describe here the 2.6 Å crystal structure of m-calpain in the Ca2+-free form, which illustrates the structural basis for the inactivity of calpain in the absence of Ca2+. It also reveals an unusual thiol protease fold, which is associated with Ca2+-binding domains through heterodimerization and a C2-like  -sandwich domain. Strikingly, the structure shows that the catalytic triad is not assembled, indicating that Ca2+-binding must induce conformational changes that re-orient the protease domains to form a functional active site. The  -helical N-terminal anchor of the catalytic subunit does not occupy the active site but inhibits its assembly and regulates Ca2+-sensitivity through association with the regulatory subunit. This Ca2+-dependent activation mechanism is clearly distinct from those of classical proteases. |
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| Keywords: calcium, calpain, cysteine proteases, protease activation, protease structure |
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