title: Ligand-promoted protein folding by biased kinetic partitioning.
abstract: Protein folding in cells occurs in the presence of high concentrations of endogenous binding partners, and exogenous binding partners have been exploited as pharmacological chaperones. A combined mathematical modeling and experimental approach shows that a ligand improves the folding of a destabilized protein by biasing the kinetic partitioning between folding and alternative fates (aggregation or degradation). Computationally predicted inhibition of test protein aggregation and degradation as a function of ligand concentration are validated by experiments in two disparate cellular systems.
authors.affiliation: Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, USA.|Department of Biochemistry &Molecular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, USA.
authors.forename: Karan S
authors.initials: KS
authors.lastname: Hingorani
authors.affiliation: Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, USA.|Department of Biochemistry &Molecular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Metcalf
authors.affiliation: Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, USA.|Department of Biochemistry &Molecular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, USA.
authors.forename: Derrick T
authors.initials: DT
authors.lastname: Deming
authors.affiliation: Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, USA.|Department of Biochemistry &Molecular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, USA.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Garman
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Evan T
authors.initials: ET
authors.lastname: Powers
authors.affiliation: Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, USA.|Department of Biochemistry &Molecular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, USA.|Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts, USA.
authors.forename: Lila M
authors.initials: LM
authors.lastname: Gierasch
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004926:Escherichia coli / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects*; D017510:Protein Folding / Q000187:drug effects*; D059748:Proteolysis / Q000187:drug effects*; D015203:Reproducibility of Results; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D014295:Trimethoprim / Q000378:metabolism / Q000494:pharmacology; D000519:alpha-Galactosidase / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D018832:Molecular Chaperones; D066329:Protein Aggregates; D017485:1-Deoxynojirimycin; D014295:Trimethoprim; C090092:migalastat; D013762:Tetrahydrofolate Dehydrogenase; C576330:GLA protein, human; D000519:alpha-Galactosidase