All About Multiple Sclerosis

More MS news articles for March 2004

The beta- and gamma-CH(2) of B27-WT's Leu(11) and Ile(18) Side Chains Play a Direct Role in Calpain Inhibition

Biochemistry. 2004 Mar 9;43(9):2596-604
Betts R, Anagli J.
Department of Pathology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, Protease Program, Karmanos Cancer Institute, Detroit, Michigan 48201, and Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan 48201.

Uncontrolled activation of calpain has been linked to tissue damage after neuronal and cardiac ischemias, traumatic spine and brain injuries, and multiple sclerosis and Alzheimer's disease.

In vivo, the activity of calpain is regulated by its endogenous inhibitor calpastatin.

The pathological role of calpain has been attributed to an imbalance between the activities of the protease and its inhibitor.

Thus, it is possible that by reimposing functional control on the protease, the progression of calpain-mediated diseases could be slowed or eliminated.

B27-WT is a 27-residue peptide (DPMSSTYIEELGKREVTIPPKYRELLA) derived from calpastatin that was previously shown to be a potent inhibitor of micro- and m-calpain.

Recently, we identified two hot spots (Leu(11)-Gly(12) and Thr(17)-Ile(18)-Pro(19)) within which the amino acid residues that are key to B27-WT's bioactivity are clustered.

In the work described here, the most critical residues of B27-WT, Leu(11) and Ile(18), were further probed to determine the nature of their interaction with calpain.

Our results demonstrate that the side chains of both residues interact with hydrophobic pockets in calpain and that each of these interactions is indispensable for effective inhibition of calpain.

Direct interactions involving the beta- and gamma-CH(2)- of the Leu(11) and Ile(18) side chains, respectively, rather than the degree of side chain branching or hydrophobicity, seemed to play a significant role in the peptide's ability to inhibit calpain.

Furthermore, the minimum peptide sequence that still retained the calpain-inhibitory potency of B27-WT was found to be MSSTYIEELGKREVTIPPKYRELL.