Dataset Information

Electrostatics and Intrinsic Disorder Drive Translocon Binding of the SRP Receptor FtsY.

ABSTRACT: Integral membrane proteins in bacteria are co-translationally targeted to the SecYEG translocon for membrane insertion via the signal recognition particle (SRP) pathway. The SRP receptor FtsY and its N-terminal A domain, which is lacking in any structural model of FtsY, were studied using NMR and fluorescence spectroscopy. The A domain is mainly disordered and highly flexible; it binds to lipids via its N terminus and the C-terminal membrane targeting sequence. The central A domain binds to the translocon non-specifically and maintains disorder. Translocon targeting and binding of the A domain is driven by electrostatic interactions. The intrinsically disordered A domain tethers FtsY to the translocon, and because of its flexibility, allows the FtsY NG domain to scan a large area for binding to the NG domain of ribosome-bound SRP, thereby promoting the formation of the quaternary transfer complex at the membrane.

SUBMITTER: Lakomek NA

PROVIDER: S-EPMC5094494 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Electrostatics and Intrinsic Disorder Drive Translocon Binding of the SRP Receptor FtsY.

Lakomek Nils-Alexander NA Draycheva Albena A Bornemann Thomas T Wintermeyer Wolfgang W

Angewandte Chemie (International ed. in English) 20160627 33

Integral membrane proteins in bacteria are co-translationally targeted to the SecYEG translocon for membrane insertion via the signal recognition particle (SRP) pathway. The SRP receptor FtsY and its N-terminal A domain, which is lacking in any structural model of FtsY, were studied using NMR and fluorescence spectroscopy. The A domain is mainly disordered and highly flexible; it binds to lipids via its N terminus and the C-terminal membrane targeting sequence. The central A domain binds to the ...[more]

PMID: 27346853

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Project description:The interaction between interleukin-7 (IL-7) and its α-receptor, IL-7Rα, plays fundamental roles in the development, survival, and homeostasis of B- and T-cells. N-Linked glycosylation of human IL-7Rα enhances its binding affinity for human IL-7 300-fold versus that of the nonglycosylated receptor through an allosteric mechanism. The N-glycans of IL-7Rα do not participate directly in the binding interface with IL-7. This biophysical study involves dissection of the properties of binding of IL-7 to both nonglycosylated and glycosylated forms of the IL-7Rα extracellular domain (ECD) as functions of salt, pH, and temperature using surface plasmon resonance (SPR) spectroscopy. Interactions of IL-7 with both IL-7Rα variants display weaker binding affinities with increasing salt concentrations primarily reflected by changes in the first on rates of a two-step reaction pathway. The electrostatic parameter of the IL-7-IL-7Rα interaction is not driven by complementary charge interactions through residues at the binding interface or N-glycan composition of IL-7Rα, but presumably by favorable global charges of the two proteins. van't Hoff analysis indicates both IL-7-IL-7Rα interactions are driven by large favorable entropy changes and smaller unfavorable (nonglycosylated complex) and favorable (glycosylated complex) enthalpy changes. Eyring analysis of the IL-7-IL-7Rα interactions reveals different reaction pathways and barriers for the transition-state thermodynamics with the enthalpy and entropy changes of IL-7 binding to nonglycosylated and glycosylated IL-7Rα. There were no discernible heat capacity changes for the equilibrium or transition-state binding thermodynamics of the IL-7-IL-7Rα interactions. The results suggest that the unbound nonglycosylated IL-7Rα samples an extensive conformational landscape relative to the unbound glycosylated IL-7Rα, potentially explaining the switch from a "conformationally controlled" reaction (k(1) ∼ 10(2) M(-1) s(-1)) for the nonglycosylated interaction to a "diffusion-controlled" reaction (k(1) ∼ 10(6) M(-1) s(-1)) for the glycosylated interaction. Thus, a large favorable entropy change, a global favorable electrostatic component, and glycosylation of the receptor, albeit not at the interface, contribute significantly to the interaction between IL-7 and the IL-7Rα ECD.

Dataset Information

Electrostatics and Intrinsic Disorder Drive Translocon Binding of the SRP Receptor FtsY.

Publications

Electrostatics and Intrinsic Disorder Drive Translocon Binding of the SRP Receptor FtsY.

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