21 November 2008. In this week’s issue of Nature, two groups report the crystal structure of the calcium-dependent protease calpain in complex with its endogenous inhibitor protein, calpastatin. Tudor Moldoveanu and Douglas Green at St. Jude Children’s Research Hospital in Memphis, Tennessee, along with Kalle Gehring of McGill University in Montreal, Canada, as well as Rachael Hanna, Robert Campbell, and Peter Davies at the Queen’s University in Kingston, Ontario, have solved essentially identical structures of the calcium-bound form of the protease with its active site plugged by the calpain peptide.
The new structures help explain how the relatively floppy calpastatin protein takes the protein into a choke hold. The two well-ordered ends of the inhibitory domain grab hold of either side of calpain, sending the less structured intervening segment looping through the protease active site.
Calpains are potential targets in AD and stroke. Calpain 1 is located at synapses, and its activity increases in AD brain. Substrates for calpains include proteins that control APP production and tau phosphorylation. Calpain cleaves the Cdk5 regulator p35 to its constitutively active p25 form, which is also elevated in AD brain and appears to be involved in neurodegeneration. Calpains participate in calcium-initiated cell death, which has been implicated in neurotoxicity due to amyloid-β. A report last summer indicated that calpain inhibitors prevent the synaptic toxicity of Aβ and improve memory in a mouse model of AD (see ARF related news story).
However attractive the target, finding specific small-molecule inhibitors of these serine proteases has been difficult (reviewed in Carragher, 2006). Previous inhibitors have tended to hit other proteases as well, for example, cathepsins and even the proteasome. The detailed structure of the complex will come in handy to guide the design of new, hopefully more targeted, inhibitors.—Pat McCaffrey.
Moldoveanu T, Ghering K, Green DR. Concerted multi-pronged attack by calpastatin to occlude the catalytic cleft of heterodimeric calpains. Nature. 2008 November 20;256:404-408. Abstract
Hanna RA, Campbell RL, Davies PL. Calcium-bound structure of calpain and its mechanism of inhibition by calpastatin. Nature. 2008 November 20;256:409-412. Abstract
Mellgren RL. Enzyme knocked for a loop. Nature. 2008 November 20;256:337-338.