Selectivity Determinants of RHO GTPase Binding to IQGAPs

IQ motif-containing GTPase-activating proteins (IQGAPs) modulate a wide range of cellular processes by acting as scaffolds and driving protein components into distinct signaling networks. Their functional states have been proposed to be controlled by members of the RHO family of GTPases, among other...

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Autores principales:	Niloufar Mosaddeghzadeh, Kazem Nouri, Oliver H. F. Krumbach, Ehsan Amin, Radovan Dvorsky, Mohammad R. Ahmadian
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	IQGAP scaffold RHO GTPases CDC42 RAC1 selective bindings Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/1a5b99874fe74dca84374507ab9c68ac
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spelling	oai:doaj.org-article:1a5b99874fe74dca84374507ab9c68ac2021-11-25T17:58:13ZSelectivity Determinants of RHO GTPase Binding to IQGAPs10.3390/ijms2222125961422-00671661-6596https://doaj.org/article/1a5b99874fe74dca84374507ab9c68ac2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12596https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067IQ motif-containing GTPase-activating proteins (IQGAPs) modulate a wide range of cellular processes by acting as scaffolds and driving protein components into distinct signaling networks. Their functional states have been proposed to be controlled by members of the RHO family of GTPases, among other regulators. In this study, we show that IQGAP1 and IQGAP2 can associate with CDC42 and RAC1-like proteins but not with RIF, RHOD, or RHO-like proteins, including RHOA. This seems to be based on the distribution of charged surface residues, which varies significantly among RHO GTPases despite their high sequence homology. Although effector proteins bind first to the highly flexible switch regions of RHO GTPases, additional contacts outside are required for effector activation. Sequence alignment and structural, mutational, and competitive biochemical analyses revealed that RHO GTPases possess paralog-specific residues outside the two highly conserved switch regions that essentially determine the selectivity of RHO GTPase binding to IQGAPs. Amino acid substitution of these specific residues in RHOA to the corresponding residues in RAC1 resulted in RHOA association with IQGAP1. Thus, electrostatics most likely plays a decisive role in these interactions.Niloufar MosaddeghzadehKazem NouriOliver H. F. KrumbachEhsan AminRadovan DvorskyMohammad R. AhmadianMDPI AGarticleIQGAPscaffoldRHO GTPasesCDC42RAC1selective bindingsBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12596, p 12596 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	IQGAP scaffold RHO GTPases CDC42 RAC1 selective bindings Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	IQGAP scaffold RHO GTPases CDC42 RAC1 selective bindings Biology (General) QH301-705.5 Chemistry QD1-999 Niloufar Mosaddeghzadeh Kazem Nouri Oliver H. F. Krumbach Ehsan Amin Radovan Dvorsky Mohammad R. Ahmadian Selectivity Determinants of RHO GTPase Binding to IQGAPs
description	IQ motif-containing GTPase-activating proteins (IQGAPs) modulate a wide range of cellular processes by acting as scaffolds and driving protein components into distinct signaling networks. Their functional states have been proposed to be controlled by members of the RHO family of GTPases, among other regulators. In this study, we show that IQGAP1 and IQGAP2 can associate with CDC42 and RAC1-like proteins but not with RIF, RHOD, or RHO-like proteins, including RHOA. This seems to be based on the distribution of charged surface residues, which varies significantly among RHO GTPases despite their high sequence homology. Although effector proteins bind first to the highly flexible switch regions of RHO GTPases, additional contacts outside are required for effector activation. Sequence alignment and structural, mutational, and competitive biochemical analyses revealed that RHO GTPases possess paralog-specific residues outside the two highly conserved switch regions that essentially determine the selectivity of RHO GTPase binding to IQGAPs. Amino acid substitution of these specific residues in RHOA to the corresponding residues in RAC1 resulted in RHOA association with IQGAP1. Thus, electrostatics most likely plays a decisive role in these interactions.
format	article
author	Niloufar Mosaddeghzadeh Kazem Nouri Oliver H. F. Krumbach Ehsan Amin Radovan Dvorsky Mohammad R. Ahmadian
author_facet	Niloufar Mosaddeghzadeh Kazem Nouri Oliver H. F. Krumbach Ehsan Amin Radovan Dvorsky Mohammad R. Ahmadian
author_sort	Niloufar Mosaddeghzadeh
title	Selectivity Determinants of RHO GTPase Binding to IQGAPs
title_short	Selectivity Determinants of RHO GTPase Binding to IQGAPs
title_full	Selectivity Determinants of RHO GTPase Binding to IQGAPs
title_fullStr	Selectivity Determinants of RHO GTPase Binding to IQGAPs
title_full_unstemmed	Selectivity Determinants of RHO GTPase Binding to IQGAPs
title_sort	selectivity determinants of rho gtpase binding to iqgaps
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/1a5b99874fe74dca84374507ab9c68ac
work_keys_str_mv	AT niloufarmosaddeghzadeh selectivitydeterminantsofrhogtpasebindingtoiqgaps AT kazemnouri selectivitydeterminantsofrhogtpasebindingtoiqgaps AT oliverhfkrumbach selectivitydeterminantsofrhogtpasebindingtoiqgaps AT ehsanamin selectivitydeterminantsofrhogtpasebindingtoiqgaps AT radovandvorsky selectivitydeterminantsofrhogtpasebindingtoiqgaps AT mohammadrahmadian selectivitydeterminantsofrhogtpasebindingtoiqgaps
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Selectivity Determinants of RHO GTPase Binding to IQGAPs

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