Crystal structure of hGEF-H1 PH domain provides insight into incapability in phosphoinositide binding

Jiang, Yan; Jiang, Heli; Zhou, Shaoyang; Meng, Bingkun; Liu, Zhijie; Ouyang, Songying

doi:10.1016/j.bbrc.2016.01.150

Cited by 3 publications

(1 citation statement)

References 25 publications

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“…Over 80 Rho GEFs have been identified. Human GEF-H1 and its murine homologue Lfc are members of the Dbl family, which has Dbl homology (DH) and pleckstrin homology (PH) domains [ 19 , 24 ]. GEF-H1 usually binds to microtubules and cell-cell junctions in quiescent cells, sequestering its interaction with RhoA.…”

Section: Introductionmentioning

confidence: 99%

Reducing GEF-H1 Expression Inhibits Renal Cyst Formation, Inflammation, and Fibrosis via RhoA Signaling in Nephronophthisis

Lai

Chen

et al. 2023

IJMS

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Nephronophthisis (NPHP) is the most prevalent monogenic disease leading to end-stage renal failure in childhood. RhoA activation is involved in NPHP pathogenesis. This study explored the role of the RhoA activator guanine nucleotide exchange factor (GEF)-H1 in NPHP pathogenesis. We analyzed the expression and distribution of GEF-H1 in NPHP1 knockout (NPHP1KO) mice using Western blotting and immunofluorescence, followed by GEF-H1 knockdown. Immunofluorescence and renal histology were used to examine the cysts, inflammation, and fibrosis. A RhoA GTPase activation assay and Western blotting were used to detect the expression of downstream GTP-RhoA and p-MLC2, respectively. In NPHP1 knockdown (NPHP1KD) human kidney proximal tubular cells (HK2 cells), we detected the expressions of E-cadherin and α-smooth muscle actin (α-SMA). In vivo, increased expression and redistribution of GEF-H1, and higher levels of GTP-RhoA and p-MLC2 in renal tissue of NPHP1KO mice were observed, together with renal cysts, fibrosis, and inflammation. These changes were alleviated by GEF-H1 knockdown. In vitro, the expression of GEF-H1 and activation of RhoA were also increased, with increased expression of α-SMA and decreased E-cadherin. GEF-H1 knockdown reversed these changes in NPHP1KD HK2 cells. Thus, the GEF-H1/RhoA/MLC2 axis is activated in NPHP1 defects and may play a pivotal role in NPHP pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Reducing GEF-H1 Expression Inhibits Renal Cyst Formation, Inflammation, and Fibrosis via RhoA Signaling in Nephronophthisis

Lai

Chen

et al. 2023

IJMS

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Modeling of PH Domains and Phosphoinositides Interactions and Beyond

Feng

et al. 2018

Advances in Experimental Medicine and Biology

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Pleckstrin homology (PH) domains form a large family of protein modules within membrane-targeting domains. PH domains can function as lipid-binding modules, and in particular bind with different specificities and affinities to phosphoinositides (PIs). Understanding the association of PH domains to PIs is critical for many aspects of cellular biology. Bioinformatics and computational modeling approaches have become standard tools to study the structure and dynamics of PH domains and PIs. In this review, recent advances in the binding specificity of PH domains and their interactions with PIs, using bioinformatics tools for the prediction of PIs binding sites, performing molecular dynamics simulations to study PH domains-PIs interactions, as well as the computational inhibitor design for PH domains guided signaling pathways have been discussed.

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The RhoGEF protein Plekhg5 self-associates via its PH domain to regulate apical cell constriction

Popov,

Tao,

Chang

2024

MBoC

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RhoGEFs are critical activators of Rho family small GTPases and regulate diverse biological processes, such as cell division and tissue morphogenesis. We reported previously that the RhoGEF gene plekhg5 controls apical constriction of bottle cells at the blastopore lip during Xenopus gastrulation, but the detailed mechanism of plekhg5 action is not understood in depth. In this study, we show that localization of Plekhg5 in the apical cortex depends on its N-terminal sequences and intact guanine nucleotide exchange activity, whereas the C-terminal sequences prevent ectopic localization of the protein to the basolateral compartment. We also reveal that Plekhg5 self-associates via its PH domain, and this interaction leads to functional rescue of two mutants that lack the N-terminal region and the GEF activity, respectively, in trans. A point mutation in the PH domain corresponding to a variant associated with human disease leads to loss of self-association and failure of the mutant to induce apical constriction. Taken together, our results suggest that PH-mediated self-association and N-terminal domain-mediated subcellular localization are both crucial for the function of Plekhg5 in inducing apical constriction. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text]

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Crystal structure of hGEF-H1 PH domain provides insight into incapability in phosphoinositide binding

Cited by 3 publications

References 25 publications

Reducing GEF-H1 Expression Inhibits Renal Cyst Formation, Inflammation, and Fibrosis via RhoA Signaling in Nephronophthisis

Reducing GEF-H1 Expression Inhibits Renal Cyst Formation, Inflammation, and Fibrosis via RhoA Signaling in Nephronophthisis

Modeling of PH Domains and Phosphoinositides Interactions and Beyond

The RhoGEF protein Plekhg5 self-associates via its PH domain to regulate apical cell constriction

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