Di-Ras2 Protein Forms a Complex with SmgGDS Protein in Brain Cytosol in Order to Be in a Low Affinity State for Guanine Nucleotides

Ogita, Yoshitaka; Egami, Sachiko; Ebihara, Arisa; Ueda, Noboru; Katada, Toshiaki; Kontani, Kenji

doi:10.1074/jbc.m115.637769

Cited by 15 publications

(16 citation statements)

References 29 publications

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“…The N338 residue of SmgGDS-558, which was reported to be essential for interaction and GEF activity toward RhoA, made a hydrogen bond to the D67 residue of RhoA (Fig. 2) (7,12,19). The switch II region and some other residues, including the N-terminal (A3, R5, and K6) and Cterminal flanking region (K98 and E102) of RhoA, formed interaction networks toward SmgGDS-558 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…SmgGDS also acts as a chaperone protein for small GTPases having a CaaX motif, in addition to a GEF for Rho family proteins (5)(6)(7)(8)(9)(10). SmgGDS interacts with various small GTPases possessing a Cterminal polybasic region (PBR) upstream of the CaaX motif in a hypervariable region (HVR) (5,6,(11)(12)(13). SmgGDS is overexpressed in nonsmall cell lung carcinoma (14,15), prostate cancer (16), breast cancer (15,17), and pancreatic cancer (15).…”

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confidence: 99%

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GEF mechanism revealed by the structure of SmgGDS-558 and farnesylated RhoA complex and its implication for a chaperone mechanism

Shimizu

Toma-Fukai

Kontani

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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SmgGDS has dual functions in cells and regulates small GTPases as both a guanine nucleotide exchange factor (GEF) for the Rho family and a molecular chaperone for small GTPases possessing a C-terminal polybasic region followed by four C-terminal residues called the CaaX motif, which is posttranslationally prenylated at its cysteine residue. Our recent structural work revealed that SmgGDS folds into tandem copies of armadillo-repeat motifs (ARMs) that are not present in other GEFs. However, the precise mechanism of GEF activity and recognition mechanism for the prenylated CaaX motif remain unknown because SmgGDS does not have a typical GEF catalytic domain and lacks a pocket to accommodate a prenyl group. Here, we aimed to determine the crystal structure of the SmgGDS/farnesylated RhoA complex. We found that SmgGDS induces a significant conformational change in the switch I and II regions that opens up the nucleotide-binding site, with the prenyl group fitting into the cryptic pocket in the N-terminal ARMs. Taken together, our findings could advance the understanding of the role of SmgGDS and enable drug design strategies for targeting SmgGDS and small GTPases.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

GEF mechanism revealed by the structure of SmgGDS-558 and farnesylated RhoA complex and its implication for a chaperone mechanism

Shimizu

Toma-Fukai

Kontani

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Asn-338 of SmgGDS-558 (Asn-387 of SmgGDS-607) is a critical residue for binding to small GTPases (4,17). For example, an N338A mutant of SmgGDS-558 exhibits an inability to interact with Di-Ras2 (4).…”

Section: Smggds-558 Has Characteristic Surface Electrostatic Potentialmentioning

confidence: 99%

“…SmgGDS was originally identified as a GEF for many types of small GTPases, including Rho and Ras family members (1,2). In particular, SmgGDS interacts with small GTPases possessing a polybasic region (PBR) at the C-terminal region, such as RhoA, Rac1, Rap1A, K-Ras4B, and Di-Ras2 (3)(4)(5). SmgGDS has various roles in the regulation of small GTPases, including those in trafficking, localization, and molecular chaperone functions, in addition to its general role as a GEF.…”

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confidence: 99%

Structure-based analysis of the guanine nucleotide exchange factor SmgGDS reveals armadillo-repeat motifs and key regions for activity and GTPase binding

Shimizu

Toma-Fukai

Saijo

et al. 2017

Journal of Biological Chemistry

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Small GTPases are molecular switches that have critical biological roles and are controlled by GTPase-activating proteins and guanine nucleotide exchange factors (GEFs). The smg GDP dissociation stimulator (SmgGDS) protein functions as a GEF for the RhoA and RhoC small GTPases. SmgGDS has various regulatory roles, including small GTPase trafficking and localization and as a molecular chaperone, and interacts with many small GTPases possessing polybasic regions. Two SmgGDS splice variants, SmgGDS-558 and SmgGDS-607, differ in GEF activity and binding affinity for RhoA depending on the lipidation state, but the reasons for these differences are unclear. Here we determined the crystal structure of SmgGDS-558, revealing a fold containing tandem copies of armadillo repeats not present in other GEFs. We also observed that SmgGDS harbors distinct positively and negatively charged regions, both of which play critical roles in binding to RhoA and GEF activity. This is the first report demonstrating a relationship between the molecular function and atomic structure of SmgGDS. Our findings indicate that the two SmgGDS isoforms differ in GTPase binding and GEF activity, depending on the lipidation state, thus providing useful information about the cellular functions of SmgGDS in cells.

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“…The GTP-binding Ras-like protein 2 (Di-Ras2) is one of GTPases forming a distinct subgroup of the Ras family, and shares 30–40% overall identity with other members of the Ras family [18, 19]. Di-Ras2 forms a tight complex with SmgGDS in cytosol, which lowers its affinity for guanine nucleotides [20]. Analyses using Oncomine and The Cancer Genome Atlas (TCGA) databases show that mRNA expression levels of Di-Ras2 are significantly up-regulated in some tumors, especially ccRCC.…”

Section: Introductionmentioning

confidence: 99%

Di-Ras2 Promotes Renal Cell Carcinoma Formation by Activating the MAPK Pathway in the Absence of VHL

Rao

Liu

et al. 2019

Preprint

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Clear cell renal cell carcinoma (ccRCC) is one of the most common and lethal human urological malignancies in the world. The pathological drivers for ccRCC are still poorly understood. One of them is the Ras family of small GTPases that function as “molecular switches” in many diseases including ccRCC. Among them, Di-Ras2 encodes a 26-kDa GTPase that shares 60% homology to Ras and Rap. Yet little is known about the biological function(s) of Di-Ras2. In this study, we found that Di-Ras2 was upregulated in ccRCC, and promoted the proliferation, migration and invasion of human ccRCC cells in the absence of von Hippel-Lindau (VHL). Mechanistically, Di-Ras2 induces and regulates ccRCC formation by modulating phosphorylation of the downstream effectors and activating the MAPK signaling pathway. Moreover, Di-Ras2 interacts with E3 ubiquitin ligase, VHL, which facilitates the ubiquitination and degradation of Di-Ras2. Together, these results indicate a potential function of Di-Ras2 as an oncogene and biomarker in ccRCC, and these data provide a new perspective of the relationship between VHL and the MAPK pathway in ccRCC tumorigenesis.

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Di-Ras2 Protein Forms a Complex with SmgGDS Protein in Brain Cytosol in Order to Be in a Low Affinity State for Guanine Nucleotides

Cited by 15 publications

References 29 publications

GEF mechanism revealed by the structure of SmgGDS-558 and farnesylated RhoA complex and its implication for a chaperone mechanism

GEF mechanism revealed by the structure of SmgGDS-558 and farnesylated RhoA complex and its implication for a chaperone mechanism

Structure-based analysis of the guanine nucleotide exchange factor SmgGDS reveals armadillo-repeat motifs and key regions for activity and GTPase binding

Di-Ras2 Promotes Renal Cell Carcinoma Formation by Activating the MAPK Pathway in the Absence of VHL

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