Structural Basis of Rnd1 Binding to Plexin Rho GTPase Binding Domains (RBDs)

Wang, Hui; Hota, Prasanta Kumar; Tong, Yufeng; Li, Buren; Shen, Limin; Nedyalkova, L.; Borthakur, Susmita; Kim, SoonJeung; Tempel, W.; Buck, Matthias; Park, Hee Won

doi:10.1074/jbc.m110.197053

Cited by 36 publications

(43 citation statements)

References 55 publications

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“…The structure of the plexin-B1 RBD in complex with a Rac1 homologous GTPase, Rnd1 was determined by X-ray crystallography (47). Classical all-atom MD simulations were carried out on the two RBD–GTPase complexes and on the free proteins.…”

Section: Methods Of Analysis and Examples Of Results And Their Intmentioning

confidence: 99%

Combining NMR and Molecular Dynamics Studies for Insights into the Allostery of Small GTPase–Protein Interactions

Zhang

Bouguet‐Bonnet

Buck

2011

Methods in Molecular Biology

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Combinations of experimentally derived data from nuclear magnetic resonance spectroscopy and analyses of molecular dynamics trajectories increasingly allow us to obtain a detailed description of the molecular mechanisms by which proteins function in signal transduction. This chapter provides an introduction into these two methodologies, illustrated by example of a small GTPase–effector interaction. It is increasingly becoming clear that new insights are provided by the combination of experimental and computational methods. Understanding the structural and protein dynamical contributions to allostery will be useful for the engineering of new binding interfaces and protein functions, as well as for the design/in silico screening of chemical agents that can manipulate the function of small GTPase–protein interactions in diseases such as cancer.

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Section: Methods Of Analysis and Examples Of Results And Their Intmentioning

confidence: 99%

Combining NMR and Molecular Dynamics Studies for Insights into the Allostery of Small GTPase–Protein Interactions

Zhang

Bouguet‐Bonnet

Buck

2011

Methods in Molecular Biology

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“…The Rho GTPase RND1 has been implicated in the regulation of the actin cytoskeleton and microtubule dynamics in response to extracellular growth factors through actin reorganization in response to extracellular interactions with plexin/ semaphorin (81)(82)(83)(84). Plexin-B1 directly binds RND1.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated Glycoprotein B-Mediated Cell-Cell Fusion Disrupts Varicella-Zoster Virus and Host Gene Transcription during Infection

Oliver

Yang

Arvin

2017

J Virol

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The highly conserved herpesvirus glycoprotein complex gB/gH-gL mediates membrane fusion during virion entry and cell-cell fusion. Varicellazoster virus (VZV) characteristically forms multinucleated cells, or syncytia, during the infection of human tissues, but little is known about this process. The cytoplasmic domain of VZV gB (gBcyt) has been implicated in cell-cell fusion regulation because a gB[Y881F] substitution causes hyperfusion. gBcyt regulation is necessary for VZV pathogenesis, as the hyperfusogenic mutant gB[Y881F] is severely attenuated in human skin xenografts. In this study, gBcyt-regulated fusion was investigated by comparing melanoma cells infected with wild-type-like VZV or hyperfusogenic mutants. The gB[Y881F] mutant exhibited dramatically accelerated syncytium formation in melanoma cells caused by fusion of infected cells with many uninfected cells, increased cytoskeleton reorganization, and rapid displacement of nuclei to dense central structures compared to pOka using live-cell confocal microscopy. VZV and human transcriptomes were concurrently investigated using whole transcriptome sequencing (RNA-seq) to identify viral and cellular responses induced when gBcyt regulation was disrupted by the gB[Y881F] substitution. The expression of four vital VZV genes, ORF61 and the genes for glycoproteins gC, gE, and gI, was significantly reduced at 36 h postinfection for the hyperfusogenic mutants. Importantly, hierarchical clustering demonstrated an association of differential gene expression with dysregulated gBcyt-mediated fusion. A subset of Ras GTPase genes linked to membrane remodeling were upregulated in cells infected with the hyperfusogenic mutants. These data implicate gBcyt in the regulation of gB fusion function that, if unmodulated, triggers cellular processes leading to hyperfusion that attenuates VZV infection. IMPORTANCEThe highly infectious, human-restricted pathogen varicella-zoster virus (VZV) causes chickenpox and shingles. Postherpetic neuralgia (PHN) is a common complication of shingles that manifests as prolonged excruciating pain, which has proven difficult to treat. The formation of fused multinucleated cells in ganglia might be associated with this condition. An effective vaccine against VZV is available but not recommended for immunocompromised individuals, highlighting the need for new therapies. This study investigated the viral and cellular responses to hyperfusion, a condition where the usual constraints of cell membranes are overcome and cells form multinucleated cells. This process hinders VZV and is regulated by a viral glycoprotein, gB. A combination of live-cell imaging and next-generation genomics revealed an alteration in viral and cellular responses during hyperfusion that was caused by the loss of gB regulation. These studies reveal mechanisms central to VZV pathogenesis, potentially leading to improved therapies.

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“…Plexin C1 was expressed in both MC3T3-E1 and calvarial osteoblasts at all stages during osteoblast differentiation 17) . The plexin C1 cytoplasmic domain contains a Rho-GTPase binding domain region flanked by two GAP domains, which show RasGAP activity in vitro 29,30) . However, the contribution of Sema-7A-plexin C1 interactions to osteoblast differentiation is largely unknown.…”

Section: Expression Of Semaphorin 7a Receptors During Osteogenic Diffmentioning

confidence: 99%

Gene Expression of Semaphorin 7A During Osteogenic Differentiation in Human Dental Follicle Cells

Kato¹,

Takahashi

2016

J. Hard Tissue Biology.

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Semaphorin (Sema) 7A, also known as CDw108, is the only glycophosphatidylinositol (GPI)-linked member of the semaphorin family. It was recently suggested that Sema 7A regulates osteoblast and osteoclast differentiation, and is important for bone homeostasis. The dental follicle is an ectomesenchymal tissue that surrounds developing tooth germ, which contains osteoblastic/cementoblastic lineage committed stem/progenitor cells. The purpose of this study was to examine the gene expression of Sema 7A and its receptors, plexinC1 and -integrin, in human dental follicle cells (hDFCs) during osteogenic differentiation. We analyzed gene expression profiles between hDFCs cultures with GM and OIM on day 17. Sema 7A was the most up-regulated among the semaphorin family members in OIM culture when compared to GM culture. We confirmed the gene expression of Sema 7A in three hDFCs samples isolated from three donors using real-time PCR. Sema 7A was up-regulated in OIM culture in three hDFC samples. In addition, Sema 7A mRNA showed high levels on days 0 and 17 in hDFCs cultured in OIM, as compared to days 3 and 10, exhibiting bimodal expression during osteoblast differentiation. The expression of plexin C1 and -integrin was also up-regulated in OIM culture when compared to GM culture. These findings suggest that Sema 7A and its receptors are associated with the osteogenic differentiation of hDFCs.

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Structural Basis of Rnd1 Binding to Plexin Rho GTPase Binding Domains (RBDs)

Cited by 36 publications

References 55 publications

Combining NMR and Molecular Dynamics Studies for Insights into the Allostery of Small GTPase–Protein Interactions

Combining NMR and Molecular Dynamics Studies for Insights into the Allostery of Small GTPase–Protein Interactions

Dysregulated Glycoprotein B-Mediated Cell-Cell Fusion Disrupts Varicella-Zoster Virus and Host Gene Transcription during Infection

Gene Expression of Semaphorin 7A During Osteogenic Differentiation in Human Dental Follicle Cells

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