Background: Intrinsically disordered proteins (IDPs) are an emerging part of structural biology that has challenged the classic paradigm of structure-function relationship. Indeed, IDPs have been associated with different physiological functions and associated with several pathologies, such as polyglutamine (polyQ) related diseases. Ataxin-3 (AT3) is the smallest polyQ protein, composed by the N-terminal folded Josephin domain (JD), which is amyloidogenic on its own, and a C-terminal unstructured part. The disordered region between the polyQ and the JD, AT3182-291 plays a key role in the development of the disease.
Methods: We integrated different biophysical experimental techniques, atomistic explicit-solvent molecular dynamics (MD) simulations and graph theory to study AT3182-291 structure.
Results: AT3182-291 is a monomeric intrinsically disordered (ID) domain in solution and it is characterized by different conformational states, ascribable to pre-molten globule populations with different degrees of compactness. If isolated, it decreases the aggregation of the entire AT3.
Conclusions: We provided the first structural description of an ID domain associated to a polyQ protein and we also showed that it exerts protective effects against AT3 aggregation. This effect is likely to be induced by intermolecular interactions between AT3 and the ubiquitin-interacting motifs of AT3182-291. Electrostatic interactions play a pivotal role in regulating the topology and tertiary propensity of the fragment and hub residues have been identified.
General significance: Synergistic use of atomistic simulations and biophysical techniques should be more generally applied to the study of IDPs. Since ID domains and polyQ-proteins are intimately connected, the study here provided can be of interest for other members of the group.
Keywords: Aggregation; Ataxin-3; Intrinsically disordered; Molecular dynamics; Polyglutamine; Ubiquitin interacting motif.
© 2013 Elsevier B.V. All rights reserved.