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000912178 1001_ $$00000-0001-5786-8992$$aMosaddeghzadeh, Niloufar$$b0
000912178 245__ $$aCDC42-IQGAP Interactions Scrutinized: New Insights into the Binding Properties of the GAP-Related Domain.
000912178 260__ $$aBasel$$bMolecular Diversity Preservation International$$c2022
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000912178 520__ $$aThe 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.
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000912178 650_7 $$2Other$$aCDC42
000912178 650_7 $$2Other$$aGAP
000912178 650_7 $$2Other$$aGAP-related domain
000912178 650_7 $$2Other$$aGRD
000912178 650_7 $$2Other$$aGTPase activating protein
000912178 650_7 $$2Other$$aIQGAP
000912178 650_7 $$2Other$$aRASGAP
000912178 650_7 $$2Other$$aRHO GTPases
000912178 650_7 $$2Other$$anucleotide-independent binding
000912178 650_7 $$2Other$$ascaffold protein
000912178 650_7 $$2Other$$ascaffolding protein
000912178 650_7 $$2Other$$aswitch regions
000912178 650_7 $$2NLM Chemicals$$aGTPase-Activating Proteins
000912178 650_7 $$2NLM Chemicals$$aNucleotides
000912178 650_7 $$2NLM Chemicals$$aras GTPase-Activating Proteins
000912178 650_7 $$086-01-1$$2NLM Chemicals$$aGuanosine Triphosphate
000912178 650_7 $$0EC 3.6.5.2$$2NLM Chemicals$$acdc42 GTP-Binding Protein
000912178 650_2 $$2MeSH$$aBinding Sites
000912178 650_2 $$2MeSH$$aGTPase-Activating Proteins: metabolism
000912178 650_2 $$2MeSH$$aGuanosine Triphosphate: metabolism
000912178 650_2 $$2MeSH$$aNucleotides: metabolism
000912178 650_2 $$2MeSH$$aProtein Binding
000912178 650_2 $$2MeSH$$acdc42 GTP-Binding Protein: genetics
000912178 650_2 $$2MeSH$$acdc42 GTP-Binding Protein: metabolism
000912178 650_2 $$2MeSH$$aras GTPase-Activating Proteins: genetics
000912178 650_2 $$2MeSH$$aras GTPase-Activating Proteins: metabolism
000912178 7001_ $$00000-0002-4653-7263$$aPudewell, Silke$$b1
000912178 7001_ $$00000-0002-0689-7926$$aBazgir, Farhad$$b2
000912178 7001_ $$0P:(DE-HGF)0$$aKazemein Jasemi, Neda S$$b3
000912178 7001_ $$0P:(DE-HGF)0$$aKrumbach, Oliver H F$$b4
000912178 7001_ $$0P:(DE-Juel1)145165$$aGremer, Lothar$$b5
000912178 7001_ $$0P:(DE-Juel1)132029$$aWillbold, Dieter$$b6
000912178 7001_ $$0P:(DE-HGF)0$$aDvorsky, Radovan$$b7
000912178 7001_ $$00000-0002-2034-8894$$aAhmadian, Mohammad R$$b8$$eCorresponding author
000912178 773__ $$0PERI:(DE-600)2019364-6$$a10.3390/ijms23168842$$gVol. 23, no. 16, p. 8842 -$$n16$$p8842 -$$tInternational journal of molecular sciences$$v23$$x1422-0067$$y2022
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