Quantitative Analysis of Prenylated RhoA Interaction with Its Chaperone, RhoGDI

Tnimov, Zakir; Guo, Zhong; Gambin, Yann; Nguyen, Uyen; Wu, Yao‐Wen; Abankwa, Daniel; Stigter, Anouk; Collins, Brett M.; Waldmann, Herbert; Goody, Roger S.; Alexandrov, Kirill

doi:10.1074/jbc.m112.371294

Cited by 51 publications

(77 citation statements)

References 60 publications

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“…Prenylation is critical for the functioning of Rho proteins, as it enables them to reversibly associate with intracellular membranes [2] and promote binding to their key regulators, such as GDP exchange factors (GEFs) [3] and Rho GTPase-activating proteins (GAPs) [3,4]. An additional level of Rho regulation is brought about by the Rho GDP dissociation inhibitors (RhoGDIs) [5]. Three human RhoGDIs have been identified with the first isoform, RhoGDI-1 (here, RhoGDI), being most ubiquitously expressed and associating with most of the Rho proteins.…”

Section: Introductionmentioning

confidence: 99%

RhoGDI facilitates geranylgeranyltransferase-I-mediated RhoA prenylation

Tnimov¹,

Abankwa²,

Alexandrov³

2014

Biochemical and Biophysical Research Communications

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Section: Introductionmentioning

confidence: 99%

RhoGDI facilitates geranylgeranyltransferase-I-mediated RhoA prenylation

Tnimov¹,

Abankwa²,

Alexandrov³

2014

Biochemical and Biophysical Research Communications

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“…RhoGDIs undergo a high affinity interaction with the Rho proteins using an N-terminal regulatory arm contacting the switch regions and a C-terminal domain binding the isoprenyl group (Tnimov et al 2012). In contrast to the large number of RhoGEFs and RhoGAPs, there are only three known RhoGDIs in human (DerMardirossian and Bokoch 2005).…”

Section: Guanine Nucleotide Dissociation Inhibitorsmentioning

confidence: 98%

Classical Rho Proteins: Biochemistry of Molecular Switch Function and Regulation

Zhang

Nouri

Amin

et al. 2014

Ras Superfamily Small G Proteins: Biology and Mechanisms 1

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Rho family proteins are involved in an array of cellular processes by modulating cytoskeletal organization, transcription, and cell cycle progression. The signaling functions of Rho family proteins are based on the formation of distinctive protein-protein complexes with their regulators and effectors. A necessary precondition for such differential interactions is an intact molecular switch function, which is a hallmark of most members of the Rho family. Such classical Rho proteins cycle between an inactive GDP-bound state and an active GTP-bound state. They specifically interact via a consensus-binding sites called switch I and II with three structurally and functionally unrelated classes of regulatory proteins, such as guanine nucleotide dissociation inhibitors (GDIs), guanine nucleotide exchange factors (GEFs), and GTPase-activating proteins (GAPs). Extensive studies in the last 25 years have provided invaluable insights into the molecular mechanisms underlying regulation and signal transduction of the Rho family proteins. In this chapter, we will review common features of Rho protein regulations and highlight specific aspects of their structure-function relationships. Keywords Effector • GAP • GDI • GEF • Rho GTPase • Switch region Abbreviations AAliphatic amino acid Bcr Breakpoint cluster region protein C Cysteine CZH CDM-zizimin homology

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“…Importantly, in vivo or in vitro geranylgeranylated RhoA (RhoA-G) was prone to aggregation at micromolar concentrations, and the reported picomolar affinities of RhoA-G toward RhoGDI␣ are above the detection limit of ITC (data not shown) (14).…”

Section: Rhogdi␣ Is Endogenously Lysine Acetylated In Humanmentioning

confidence: 99%

“…The crystal structures of full-length RhoGDI␣ alone and in complex with RhoA, Cdc42, and Rac1 have been solved by NMR and by x-ray crystallography (11)(12)(13)(14). These studies revealed a modular structure of RhoGDI␣, a C-terminal immunoglobulin (Ig) domain forming a hydrophobic pocket accommodating the prenyl group of the RhoGNBPs and an N-terminal intrinsically unfolded domain.…”

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confidence: 99%

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Structural and Mechanistic Insights into the Regulation of the Fundamental Rho Regulator RhoGDIα by Lysine Acetylation

Kuhlmann

Wroblowski

Knyphausen

et al. 2016

Journal of Biological Chemistry

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Rho proteins are small GTP/GDP-binding proteins primarily involved in cytoskeleton regulation. Their GTP/GDP cycle is often tightly connected to a membrane/cytosol cycle regulated by the Rho guanine nucleotide dissociation inhibitor ␣ (RhoGDI␣). RhoGDI␣ has been regarded as a housekeeping regulator essential to control homeostasis of Rho proteins. Recent proteomic screens showed that RhoGDI␣ is extensively lysine-acetylated. Here, we present the first comprehensive structural and mechanistic study to show how RhoGDI␣ function is regulated by lysine acetylation. We discover that lysine acetylation impairs Rho protein binding and increases guanine nucleotide exchange factor-catalyzed nucleotide exchange on RhoA, these two functions being prerequisites to constitute a bona fide GDI displacement factor. RhoGDI␣ acetylation interferes with Rho signaling, resulting in alteration of cellular filamentous actin. Finally, we discover that RhoGDI␣ is endogenously acetylated in mammalian cells, and we identify CBP, p300, and pCAF as RhoGDI␣-acetyltransferases and Sirt2 and HDAC6 as specific deacetylases, showing the biological significance of this post-translational modification.

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Quantitative Analysis of Prenylated RhoA Interaction with Its Chaperone, RhoGDI

Cited by 51 publications

References 60 publications

RhoGDI facilitates geranylgeranyltransferase-I-mediated RhoA prenylation

RhoGDI facilitates geranylgeranyltransferase-I-mediated RhoA prenylation

Classical Rho Proteins: Biochemistry of Molecular Switch Function and Regulation

Structural and Mechanistic Insights into the Regulation of the Fundamental Rho Regulator RhoGDIα by Lysine Acetylation

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