Calcium-induced tripartite binding of intrinsically disordered calpastatin to its cognate enzyme, calpain.
The activity of calpain is controlled by the free intracellular calcium level and by the protein's intrinsically disordered endogenous inhibitor, calpastatin, mediated by short conserved segments: subdomains A-C. The exact binding mode of calpastatin to the enzyme has until now been unclear. Our NMR data of the 141 amino acid long inhibitor, with and without calcium and calpain, have revealed structural changes and a tripartite binding mode, in which the disordered inhibitor wraps around, and contacts, the enzyme at three points, facilitated by flexible linkers. This unprecedented binding mode permits a unique combination of specificity, speed and binding strength in regulation.
Institute of Chemistry, Laboratory of Structural Chemistry and Biology, Eötvös Loránd University, Budapest, Hungary.
Róbert
R
Kiss
Zoltán
Z
Bozoky
Dénes
D
Kovács
Gergely
G
Róna
Péter
P
Friedrich
Péter
P
Dvortsák
Rüdiger
R
Weisemann
Rudinger
R
Weisemann
Péter
P
Tompa
András
A
Perczel
D002118:Calcium / Q000737:chemistry*; D002135:Calcium-Binding Proteins / Q000737:chemistry*; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation
D002135:Calcium-Binding Proteins; C033668:calpastatin; D002154:Calpain; D002118:Calcium