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@ARTICLE{Mosaddeghzadeh:912178,
      author       = {Mosaddeghzadeh, Niloufar and Pudewell, Silke and Bazgir,
                      Farhad and Kazemein Jasemi, Neda S and Krumbach, Oliver H F
                      and Gremer, Lothar and Willbold, Dieter and Dvorsky, Radovan
                      and Ahmadian, Mohammad R},
      title        = {{CDC}42-{IQGAP} {I}nteractions {S}crutinized: {N}ew
                      {I}nsights into the {B}inding {P}roperties of the
                      {GAP}-{R}elated {D}omain.},
      journal      = {International journal of molecular sciences},
      volume       = {23},
      number       = {16},
      issn         = {1422-0067},
      address      = {Basel},
      publisher    = {Molecular Diversity Preservation International},
      reportid     = {FZJ-2022-05394},
      pages        = {8842 -},
      year         = {2022},
      abstract     = {The IQ motif-containing GTPase-activating protein (IQGAP)
                      family composes of three highly-related and evolutionarily
                      conserved paralogs (IQGAP1, IQGAP2 and IQGAP3), which fine
                      tune as scaffolding proteins numerous fundamental cellular
                      processes. IQGAP1 is described as an effector of CDC42,
                      although its effector function yet re-mains unclear.
                      Biophysical, biochemical and molecular dynamic simulation
                      studies have proposed that IQGAP RASGAP-related domains
                      (GRDs) bind to the switch regions and the insert helix of
                      CDC42 in a GTP-dependent manner. Our kinetic and equilibrium
                      studies have shown that IQGAP1 GRD binds, in contrast to its
                      C-terminal 794 amino acids (called C794), CDC42 in a
                      nucleotide-independent manner indicating a binding outside
                      the switch regions. To resolve this discrepancy and move
                      beyond the one-sided view of GRD, we carried out affinity
                      measurements and a systematic mutational analysis of the
                      interfacing residues between GRD and CDC42 based on the
                      crystal structure of the IQGAP2 GRD-CDC42Q61L GTP complex.
                      We determined a 100-fold lower affinity of the GRD1 of
                      IQGAP1 and of GRD2 of IQGAP2 for CDC42 mGppNHp in comparison
                      to C794/C795 proteins. Moreover, partial and major mutation
                      of CDC42 switch regions substantially affected C794/C795
                      binding but only a little GRD1 and remarkably not at all the
                      GRD2 binding. However, we clearly showed that GRD2
                      contributes to the overall affinity of C795 by using a 11
                      amino acid mutated GRD variant. Furthermore, the GRD1
                      binding to the CDC42 was abolished using specific point
                      mutations within the insert helix of CDC42 clearly
                      supporting the notion that CDC42 binding site(s) of IQGAP
                      GRD lies outside the switch regions among others in the
                      insert helix. Collectively, this study provides further
                      evidence for a mechanistic framework model that is based on
                      a multi-step binding process, in which IQGAP GRD might act
                      as a 'scaffolding domain' by binding CDC42 irrespective of
                      its nucleotide-bound forms, followed by other IQGAP domains
                      downstream of GRD that act as an effector domain and is in
                      charge for a GTP-dependent interaction with CDC42.},
      keywords     = {Binding Sites / GTPase-Activating Proteins: metabolism /
                      Guanosine Triphosphate: metabolism / Nucleotides: metabolism
                      / Protein Binding / cdc42 GTP-Binding Protein: genetics /
                      cdc42 GTP-Binding Protein: metabolism / ras
                      GTPase-Activating Proteins: genetics / ras GTPase-Activating
                      Proteins: metabolism / CDC42 (Other) / GAP (Other) /
                      GAP-related domain (Other) / GRD (Other) / GTPase activating
                      protein (Other) / IQGAP (Other) / RASGAP (Other) / RHO
                      GTPases (Other) / nucleotide-independent binding (Other) /
                      scaffold protein (Other) / scaffolding protein (Other) /
                      switch regions (Other) / GTPase-Activating Proteins (NLM
                      Chemicals) / Nucleotides (NLM Chemicals) / ras
                      GTPase-Activating Proteins (NLM Chemicals) / Guanosine
                      Triphosphate (NLM Chemicals) / cdc42 GTP-Binding Protein
                      (NLM Chemicals)},
      cin          = {IBI-7},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5244 - Information Processing in Neuronal Networks
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5244},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36012107},
      pmc          = {pmc:PMC9408373},
      UT           = {WOS:000845717700001},
      doi          = {10.3390/ijms23168842},
      url          = {https://juser.fz-juelich.de/record/912178},
}