Dr. Peter L. Davies, Queen's University, Department of Biochemistry

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Queen's University Peter L. Davies
Professor of Biochemistry & Biology

CALPAINS - calcium-dependent cysteine proteases

Fig. 1. Model of calpain showing the known calcium binding sites

This diagram is a composite of the two ubiquitous mammalian calpain isoforms, mu-calpain and m-calpain. The protease core (bounded by the dotted line) is the papain-like region of calpain. It contains two domains (I&II) in blue and cyan, respectively. In the calcium-free form (not shown), the active site cleft is wedged open into a catalytically inactive configuration. We have recently discovered two novel calcium-binding sites, one on either side of the cleft (Moldoveanu et al. 2002). When calcium (yellow or red spheres) cooperatively binds to these sites, the wedge is removed, and the cleft closes into its active form shown here.

The protease core is common to all calpains and is their defining characteristic. In mu- and m-calpain it is followed in the large (80 kDa) by two other domains: domains III (green) and IV (yellow). Domain III is also thought to bind calcium and is structurally similar to a membrane-binding domain found in some phopholipases and protein kinases. The C-terminal domain (IV) contains five EF-hand motifs (yellow) and binds three or four calcium ions. The fifth EF-hand is used as a dimerization interface to bind to the equivalent region of domain VI. This second penta-EF-hand domain (copper) is the C-terminal portion of the small subunit. The N-terminal region (not shown) is an unstructured glycine-rich sequence. The circular arrangement of domains is completed by a contact between the N-terminal anchor helix (red cylinder) and domain VI.

Moldoveanu, T., Hosfield, C.M., Lim, D., Elce, J.S., Jia, Z. and Davies, P.L. “A Ca2+ Switch Aligns the Active Site of Calpain”. (2002) Cell 108, 649-660.

Moldoveanu, T., Hosfield, C.M., Jia, Z., Elce, S.J. and Davies, P.L. “Ca2+-induced structural changes in rat m-calpain revealed by partial proteolysis”. (2001) Biochim. Biophys. Acta 1545, 245-254.

Studying the binding of calpastatin inhibiting domains to calpain using surface plasma resonance.

Best Candidates for co-crystallization

How calpain is inhibited by its natural inhibitor, calpastitin.

Cast 4 Bound to Calpain 2

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