Does intrinsically disordered caldesmon bind calmodulin via the “buttons on a string” mechanism?

We show here that chicken gizzard caldesmon (CaD) and its C-terminal domain (residues 636-771, CaD₁₃₆) are intrinsically disordered proteins. The computational and experimental analyses of the wild type CaD₁₃₆ and series of its single tryptophan mutants (W674A, W707A, and W737A) and a double tryptophan mutant (W674A/W707A) suggested that although the interaction of CaD₁₃₆ with calmodulin (CaM) can be driven by the non-specific electrostatic attraction between these oppositely charged molecules, the specificity of CaD₁₃₆-CaM binding is likely to be determined by the specific packing of important CaD₁₃₆ tryptophan residues at the CaD₁₃₆-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 CaD₁₃₆ and the CaM is solidified in a “snapping buttons” manner by specific packing of the CaD₁₃₆ “pliable buttons” (which are the short segments of fluctuating local structure condensed around the tryptophan residues) at the CaD₁₃₆-CaM interface. Our data also show that all three “buttons” are important for binding, since mutation of any of the tryptophans affects CaD₁₃₆-CaM binding and since CaD₁₃₆ remains CaM-buttoned even when two of the three tryptophans are mutated to alanines.