title: Disorder drives cooperative folding in a multidomain protein.
abstract: Many human proteins contain intrinsically disordered regions, and disorder in these proteins can be fundamental to their function-for example, facilitating transient but specific binding, promoting allostery, or allowing efficient posttranslational modification. SasG, a multidomain protein implicated in host colonization and biofilm formation in Staphylococcus aureus, provides another example of how disorder can play an important role. Approximately one-half of the domains in the extracellular repetitive region of SasG are intrinsically unfolded in isolation, but these E domains fold in the context of their neighboring folded G5 domains. We have previously shown that the intrinsic disorder of the E domains mediates long-range cooperativity between nonneighboring G5 domains, allowing SasG to form a long, rod-like, mechanically strong structure. Here, we show that the disorder of the E domains coupled with the remarkable stability of the interdomain interface result in cooperative folding kinetics across long distances. Formation of a small structural nucleus at one end of the molecule results in rapid structure formation over a distance of 10 nm, which is likely to be important for the maintenance of the structural integrity of SasG. Moreover, if this normal folding nucleus is disrupted by mutation, the interdomain interface is sufficiently stable to drive the folding of adjacent E and G5 domains along a parallel folding pathway, thus maintaining cooperative folding.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Dominika T
authors.initials: DT
authors.lastname: Gruszka
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Carolina A T F
authors.initials: CA
authors.lastname: Mendonça
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Paci
authors.affiliation: Department of Biology, University of York, York YO10 5DD, United Kingdom.
authors.forename: Fiona
authors.initials: F
authors.lastname: Whelan
authors.affiliation: Department of Biology, University of York, York YO10 5DD, United Kingdom.
authors.forename: Judith
authors.initials: J
authors.lastname: Hawkhead
authors.affiliation: Department of Biology, University of York, York YO10 5DD, United Kingdom.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Potts
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; jc162@cam.ac.uk.
authors.forename: Jane
authors.initials: J
authors.lastname: Clarke
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics; D064267:Intrinsically Disordered Proteins / Q000737:chemistry* / Q000235:genetics; D007700:Kinetics; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D011487:Protein Conformation; D011489:Protein Denaturation; D000072417:Protein Domains; D017510:Protein Folding; D055550:Protein Stability; D058767:Protein Unfolding
chemical_list: D001426:Bacterial Proteins; D064267:Intrinsically Disordered Proteins; D008565:Membrane Proteins; C524374:SasG protein, Staphylococcus aureus
keywords: IDP; cooperativity; parallel pathways; protein engineering; protein folding