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NANOSCALE PROTEIN DYNAMICS AND LONG-RANGE ALLOSTERY IN CELL SIGNALING

NANOSCALE PROTEIN DYNAMICS AND LONG-RANGE ALLOSTERY IN CELL SIGNALING Zimei Bu 1 and David J. E. Callaway 1,2 1 City College of New York and 2 New York University School of Medicine.

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NANOSCALE PROTEIN DYNAMICS AND LONG-RANGE ALLOSTERY IN CELL SIGNALING

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  1. NANOSCALE PROTEIN DYNAMICS AND LONG-RANGE ALLOSTERY IN CELL SIGNALING Zimei Bu1 and David J. E. Callaway1,2 1 City College of New York and 2New York University School of Medicine

  2. Multiple domains in proteins give rise to a great deal of flexibility and mobility, leading to protein domain dynamics. • Nanoscale domain motions can onlybe directly observed using spectra measured by neutron spin echo spectroscopy (our new frontier!). They are essential for: • nanoscale allostery • catalysis •     regulatory activity •     transport of metabolites •     formation of protein assemblies •     cellular locomotion

  3. 57.1 Å PDZ1 CT PDZ2 45.8 Å NHERF1 is an elongated protein with multiple modular domains PDZ domains CT PDZ1 PDZ2 90O NHERF1 from SAXS

  4. Structural changes in NHERF1 upon binding to ezrin NHERF1 PDZ2 PDZ1 Ezrin 110 Å Ezrin-induces long-range interdomain allostery in NHERF1

  5. Applying neutron spin echo spectroscopy to study long-range coupled protein domain motion Ferenc Mezei Nanosecond to microsecond time scales 10-1000 Å: nanolength scales

  6. Shape fluctuations in a protein thatONLY NSE can see!

  7. Protein motion—low Reynolds number Overdamped creeping motions--(badminton at bottom of molasses pool, not a cruise ship crossing the Atlantic!) Effective diffusion constant Deff(Q)

  8. The Q dependence of the decay rates of the NSE measured correlation functions is defined by the mobility tensor Mobility tensor H defines dynamics— our new technique!

  9. Mobility tensor v= H F H is the mobility tensor, and yields the velocity of a domain given the force applied on it or another subunit. NSE yields H, given structure. (Bu et al, PNAS, 2005)

  10. The dynamics of (unbound) NHERF1 alone is well described by a rigid-body model PDZ2 CT PDZ1 NHERF1 Farago et al Biophys J 2010 Only inputs to calculations are diffusion constant from PFG NMR and SANS coordinates—no need to fit NSE data or use MD!

  11. Binding to ezrin activates inter-domain motions in NHERF1 more than 100 Å away!! PDZ2 CT Rigid body PDZ1 FERM Farago et al Biophys J 2010

  12. CT FERM Binding to FERM activates inter-domain motions in NHERF1 - A simple four-point model describes all 80 Å PDZ2 59 Å PDZ1 110 Å

  13. Binding to ezrin activates nanoscale inter-domain motions in NHERF1 NHERF1 PDZ2 PDZ1 Ezrin 110 Å

  14. Neutron spin echo spectroscopy allows us to see coupled interdomain motion in proteins for the very first time • Our analyses show that these motions can be revealed by utilizing nonequilibrium statistical mechanics (mobility tensor)—no need for mnolecular dynamics or multiparameter fits

  15. Acknowledgements ILL, NIST, and ORNL NIH

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