title: The conformational ensemble of the disordered and aggregation-protective 182-291 region of ataxin-3.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy. Electronic address: gaetano.invernizzi@unimib.it.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Invernizzi
authors.forename: Matteo
authors.initials: M
authors.lastname: Lambrughi
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Regonesi
authors.forename: Paolo
authors.initials: P
authors.lastname: Tortora
authors.forename: Elena
authors.initials: E
authors.lastname: Papaleo
mesh_terms: D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D009687:Nuclear Proteins / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry*
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010455:Peptides; D012097:Repressor Proteins; C097188:polyglutamine
keywords: Aggregation; Ataxin-3; Intrinsically disordered; Molecular dynamics; Polyglutamine; Ubiquitin interacting motif