Hauptseite > Publikationsdatenbank > CDC42-IQGAP Interactions Scrutinized: New Insights into the Binding Properties of the GAP-Related Domain. > print

001     912178
005     20230123110751.0
024 7 _ |a 10.3390/ijms23168842
|2 doi
024 7 _ |a pmid:36012107
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024 7 _ |a pmc:PMC9408373
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024 7 _ |a 1422-0067
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024 7 _ |a 1661-6596
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024 7 _ |a 2128/32917
|2 Handle
024 7 _ |a WOS:000845717700001
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037 _ _ |a FZJ-2022-05394
041 _ _ |a English
082 _ _ |a 540
100 1 _ |a Mosaddeghzadeh, Niloufar
|0 0000-0001-5786-8992
|b 0
245 _ _ |a CDC42-IQGAP Interactions Scrutinized: New Insights into the Binding Properties of the GAP-Related Domain.
260 _ _ |a Basel
|c 2022
|b Molecular Diversity Preservation International
336 7 _ |a article
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336 7 _ |a Output Types/Journal article
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336 7 _ |a Journal Article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a 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.
536 _ _ |a 5244 - Information Processing in Neuronal Networks (POF4-524)
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|c POF4-524
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588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: juser.fz-juelich.de
650 _ 7 |a CDC42
|2 Other
650 _ 7 |a GAP
|2 Other
650 _ 7 |a GAP-related domain
|2 Other
650 _ 7 |a GRD
|2 Other
650 _ 7 |a GTPase activating protein
|2 Other
650 _ 7 |a IQGAP
|2 Other
650 _ 7 |a RASGAP
|2 Other
650 _ 7 |a RHO GTPases
|2 Other
650 _ 7 |a nucleotide-independent binding
|2 Other
650 _ 7 |a scaffold protein
|2 Other
650 _ 7 |a scaffolding protein
|2 Other
650 _ 7 |a switch regions
|2 Other
650 _ 7 |a GTPase-Activating Proteins
|2 NLM Chemicals
650 _ 7 |a Nucleotides
|2 NLM Chemicals
650 _ 7 |a ras GTPase-Activating Proteins
|2 NLM Chemicals
650 _ 7 |a Guanosine Triphosphate
|0 86-01-1
|2 NLM Chemicals
650 _ 7 |a cdc42 GTP-Binding Protein
|0 EC 3.6.5.2
|2 NLM Chemicals
650 _ 2 |a Binding Sites
|2 MeSH
650 _ 2 |a GTPase-Activating Proteins: metabolism
|2 MeSH
650 _ 2 |a Guanosine Triphosphate: metabolism
|2 MeSH
650 _ 2 |a Nucleotides: metabolism
|2 MeSH
650 _ 2 |a Protein Binding
|2 MeSH
650 _ 2 |a cdc42 GTP-Binding Protein: genetics
|2 MeSH
650 _ 2 |a cdc42 GTP-Binding Protein: metabolism
|2 MeSH
650 _ 2 |a ras GTPase-Activating Proteins: genetics
|2 MeSH
650 _ 2 |a ras GTPase-Activating Proteins: metabolism
|2 MeSH
700 1 _ |a Pudewell, Silke
|0 0000-0002-4653-7263
|b 1
700 1 _ |a Bazgir, Farhad
|0 0000-0002-0689-7926
|b 2
700 1 _ |a Kazemein Jasemi, Neda S
|0 P:(DE-HGF)0
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700 1 _ |a Krumbach, Oliver H F
|0 P:(DE-HGF)0
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700 1 _ |a Gremer, Lothar
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700 1 _ |a Willbold, Dieter
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700 1 _ |a Dvorsky, Radovan
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700 1 _ |a Ahmadian, Mohammad R
|0 0000-0002-2034-8894
|b 8
|e Corresponding author
773 _ _ |a 10.3390/ijms23168842
|g Vol. 23, no. 16, p. 8842 -
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|p 8842 -
|t International journal of molecular sciences
|v 23
|y 2022
|x 1422-0067
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