Post date: Jun 27, 2015 5:26:16 PM
Biochim Biophys Acta. 2013 Nov;1830(11):5236-47. doi: 10.1016/j.bbagen.2013.07.007. Epub 2013 Jul 25.
Invernizzi G, Lambrughi M, Regonesi ME, Tortora P, Papaleo E
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.
We integrated different biophysical experimental techniques, atomistic explicit-solvent molecular dynamics (MD) simulations and graph theory to study AT3182-291 structure.
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.
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.
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.
http://linkinghub.elsevier.com/retrieve/pii/S0304-4165(13)00310-3
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