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.