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@ARTICLE{Panwalkar:283504,
      author       = {Panwalkar, Vineet and Neudecker, Philipp and Schmitz,
                      Michael and Lecher, Justin and Schulte, Marianne and Medini,
                      Karima and Stoldt, Matthias and Brimble, Margaret A and
                      Willbold, Dieter and Dingley, Andrew J},
      title        = {{T}he {N}edd4-1 {WW} {D}omain {R}ecognizes the {PY} {M}otif
                      {P}eptide through {C}oupled {F}olding and {B}inding
                      {E}quilibria.},
      journal      = {Biochemistry},
      volume       = {55},
      number       = {4},
      issn         = {1520-4995},
      address      = {Columbus, Ohio},
      publisher    = {American Chemical Society},
      reportid     = {FZJ-2016-01837},
      pages        = {659 - 674},
      year         = {2016},
      abstract     = {The four WW domains of human Nedd4-1 (neuronal precursor
                      cell expressed developmentally downregulated gene 4-1)
                      interact with the PPxY (PY) motifs of the human epithelial
                      Na(+) channel (hENaC) subunits, with the third WW domain
                      (WW3*) showing the highest affinity. We have shown
                      previously that the α-hENaC PY motif binding interface of
                      WW3* undergoes conformational exchange on the millisecond
                      time scale, indicating that conformational sampling plays a
                      role in peptide recognition. To further understand this
                      role, the structure and dynamics of hNedd4-1 WW3* were
                      investigated. The nuclear Overhauser effect-derived
                      structure of apo-WW3* resembles the domain in complex with
                      the α-hENaC peptide, although particular side chain
                      conformations change upon peptide binding, which was further
                      investigated by molecular dynamics simulations. Model-free
                      analysis of the (15)N nuclear magnetic resonance spin
                      relaxation data showed that the apo and peptide-bound states
                      of WW3* have similar backbone picosecond to nanosecond time
                      scale dynamics. However, apo-WW3* exhibits pronounced
                      chemical exchange on the millisecond time scale that is
                      quenched upon peptide binding. (1)HN and (15)N
                      Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion
                      experiments at various temperatures revealed that apo-WW3*
                      exists in an equilibrium between the natively folded peptide
                      binding-competent state and a random coil-like denatured
                      state. The thermodynamics of the folding equilibrium was
                      determined by fitting a thermal denaturation profile
                      monitored by circular dichroism spectroscopy in combination
                      with the CPMG data, leading to the conclusion that the
                      unfolded state is populated to $∼20\%$ at 37 °C. These
                      results show that the binding of the hNedd4-1 WW3* domain to
                      α-hENaC is coupled to the folding equilibrium.},
      cin          = {ICS-6},
      ddc          = {570},
      cid          = {I:(DE-Juel1)ICS-6-20110106},
      pnm          = {553 - Physical Basis of Diseases (POF3-553)},
      pid          = {G:(DE-HGF)POF3-553},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26685112},
      UT           = {WOS:000369471800005},
      doi          = {10.1021/acs.biochem.5b01028},
      url          = {https://juser.fz-juelich.de/record/283504},
}