title: Dynamic periplasmic chaperone reservoir facilitates biogenesis of outer membrane proteins.
abstract: Outer membrane protein (OMP) biogenesis is critical to bacterial physiology because the cellular envelope is vital to bacterial pathogenesis and antibiotic resistance. The process of OMP biogenesis has been studied in vivo, and each of its components has been studied in isolation in vitro. This work integrates parameters and observations from both in vivo and in vitro experiments into a holistic computational model termed "Outer Membrane Protein Biogenesis Model" (OMPBioM). We use OMPBioM to assess OMP biogenesis mathematically in a global manner. Using deterministic and stochastic methods, we are able to simulate OMP biogenesis under varying genetic conditions, each of which successfully replicates experimental observations. We observe that OMPs have a prolonged lifetime in the periplasm where an unfolded OMP makes, on average, hundreds of short-lived interactions with chaperones before folding into its native state. We find that some periplasmic chaperones function primarily as quality-control factors; this function complements the folding catalysis function of other chaperones. Additionally, the effective rate for the β-barrel assembly machinery complex necessary for physiological folding was found to be higher than has currently been observed in vitro. Overall, we find a finely tuned balance between thermodynamic and kinetic parameters maximizes OMP folding flux and minimizes aggregation and unnecessary degradation. In sum, OMPBioM provides a global view of OMP biogenesis that yields unique insights into this essential pathway.
authors.affiliation: T. C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Costello
authors.affiliation: T. C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218.
authors.forename: Ashlee M
authors.initials: AM
authors.lastname: Plummer
authors.affiliation: T. C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Fleming
authors.affiliation: T. C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218 karen.fleming@jhu.edu.
authors.forename: Karen G
authors.initials: KG
authors.lastname: Fleming
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000096:biosynthesis* / Q000737:chemistry; D002352:Carrier Proteins / Q000502:physiology; D029968:Escherichia coli Proteins / Q000502:physiology; D006360:Heat-Shock Proteins / Q000502:physiology; D018832:Molecular Chaperones / Q000502:physiology*; D019696:Peptidylprolyl Isomerase / Q000502:physiology; D019897:Periplasm / Q000378:metabolism*; D033903:Periplasmic Proteins / Q000502:physiology; D066329:Protein Aggregates; D017510:Protein Folding; D012697:Serine Endopeptidases / Q000502:physiology; D013269:Stochastic Processes
chemical_list: D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D029968:Escherichia coli Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D033903:Periplasmic Proteins; D066329:Protein Aggregates; C061682:DegP protease; D012697:Serine Endopeptidases; C490900:SurA protein, E coli; D019696:Peptidylprolyl Isomerase
keywords: BAM; OMP biogenesis; kinetic model; membrane protein folding; β-barrel