Intrinsically disordered caldesmon binds calmodulin via the “buttons on a string” mechanism

We show here that chicken gizzard caldesmon (CaD) and its C-terminal domain (residues 636–771, CaD 136 ) are intrinsically disordered proteins. The computational and experimental analyses of the wild type CaD 136 and series of its single tryptophan mutants (W674A, W707A, and W737A) and a double tryptophan mutant (W674A/W707A) suggested that although the interaction of CaD 136 with calmodulin (CaM) can be driven by the non-specific electrostatic attraction between these oppositely charged molecules, the specificity of CaD 136 -CaM binding is likely to be determined by the specific packing of important CaD 136 tryptophan residues at the CaD 136 -CaM interface. It is suggested that this interaction can be described as the “buttons on a charged string” model, where the electrostatic attraction between the intrinsically disordered CaD 136 and the CaM is solidified in a “snapping buttons” manner by specific packing of the CaD 136 “pliable buttons” (which are the short segments of fluctuating local structure condensed around the tryptophan residues) at the CaD 136 -CaM interface. Our data also show that all three “buttons” are important for binding, since mutation of any of the tryptophans affects CaD 136 -CaM binding and since CaD 136 remains CaM-buttoned even when two of the three tryptophans are mutated to alanines.