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Role of Hsp70 ATPase Domain Intrinsic Dynamics and Sequence Evolution in Enabling its Functional Interactions with NEFs

Figure 4

Comparison of experimentally observed and computationally predicted structural changes in the Hsp70 ATPase domain.

Experimental changes are illustrated for BAG-1-bound and free forms of the bovine Hsp70 ATPase domain (respective PDB Ids: 1HX1 and 1HPM). Computational results are obtained by the ANM applied to the respective two structures. (a) Structural alignment of NEF-bound and unbound ATPase fragments. The unbound ATPase fragment (1HPM) is colored gray. The NEF-bound ATPase fragment (1HX1) is color-coded according to its extent of deformation with respect to the unbound ATPase, the regions showing the largest deformation being colored red, and those unchanged, blue. The distance between Ala60 and Arg258 Cα-atoms is 5.0 Å in the closed form and 10.9Å in the open form. Panel b displays the results for the unbound (black) and BAG-1-bound (red) ATPase domain. The solid curve represents the correlation cosine between the experimentally observed deformation vector d and the ANM modes 1–20 accessible to the ATPase domain (either NEF-bound or -free). The curve with circles describes the cumulative overlap (Equation 2). A subset of 6 slow modes accessible to the unbound form ensures the passage to the NEF-bound conformer with an overlap of 0.86. The NEF-bound form exhibits an even stronger potential to be reconfigured back to its closed form, consistent with the preferred conformation of the ATPase domain in the absence of NEF binding: top ranking two modes yield a cumulative overlap of 0.88 with the experimental deformation d.

Figure 4