Analysis of the interactions between GMF and Arp2/3 complex in two binding sites by molecular dynamics simulation

Popinako, A. V.; Antonov, M. Yu.; Dibrova, Daria V.; Chemeris, Angelina; Sokolova, Olga S.

doi:10.1016/j.bbrc.2018.01.080

Cited by 10 publications

(7 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This structure reveals that GMF directly contacts the Arp2 and p40/ARPC1 subunits, which is presumed to represent GMF’s high affinity binding site on Arp2/3 complex, and suggests that surfaces on Arp2 may have co-evolved with GMF to maintain GMF interactions while excluding cofilin interactions [31]. A recent study using molecular dynamics simulations provides additional support for the existence of a second, lower affinity binding site for GMF on Arp2/3 complex, that involves interactions with the Arp3 subunit [34].…”

Section: Mechanism Of Gmf-induced Debranchingmentioning

confidence: 99%

GMF as an Actin Network Remodeling Factor

Goode

Sweeney

Eskin

2018

Trends in Cell Biology

View full text Add to dashboard Cite

Glia maturation factor (GMF) has recently been established as a regulator of the actin cytoskeleton with a unique role in remodeling actin network architecture. Conserved from yeast to mammals, GMF is one of five members of the ADF-H family of actin regulatory proteins, which includes ADF/cofilin, Abp1/Drebrin, Twinfilin, and Coactosin. GMF does not bind actin, but instead binds the Arp2/3 complex with high affinity. Through this association, GMF catalyzes the debranching of actin filament networks and inhibits actin nucleation by Arp2/3 complex. Here, we discuss GMF's emerging role in controlling actin filament spatial organization and dynamics underlying cell motility, endocytosis, and other biological processes. Further, we attempt to reconcile these functions with its earlier characterization as a cell differentiation factor.

show abstract

Section: Mechanism Of Gmf-induced Debranchingmentioning

confidence: 99%

GMF as an Actin Network Remodeling Factor

Goode

Sweeney

Eskin

2018

Trends in Cell Biology

View full text Add to dashboard Cite

show abstract

“…Interestingly, these are the same two sites on Arp2/3 complex proposed to bind GMF (Fig. 6c ) 42 , 43 , 50 , 51 . Thus, the Class 1 structure of Abp1–Arp2/3 provides structural support for our model that the ADFH domain of Abp1 competes with GMF for Arp2/3 binding to protect branches from GMF-induced debranching.…”

Section: Resultsmentioning

confidence: 60%

Abp1 promotes Arp2/3 complex-dependent actin nucleation and stabilizes branch junctions by antagonizing GMF

et al. 2018

View full text Add to dashboard Cite

Formation and turnover of branched actin networks underlies cell migration and other essential force-driven processes. Type I nucleation-promoting factors (NPFs) such as WASP recruit actin monomers to Arp2/3 complex to stimulate nucleation. In contrast, mechanisms of type II NPFs such as Abp1 (also known as HIP55 and Drebrin-like protein) are less well understood. Here, we use single-molecule analysis to investigate yeast Abp1 effects on Arp2/3 complex, and find that Abp1 strongly enhances Arp2/3-dependent branch nucleation by stabilizing Arp2/3 on sides of mother filaments. Abp1 binds dynamically to filament sides, with sub-second lifetimes, yet associates stably with branch junctions. Further, we uncover a role for Abp1 in protecting filament junctions from GMF-induced debranching by competing with GMF for Arp2/3 binding. These data, combined with EM structures of Abp1 dimers bound to Arp2/3 complex in two different conformations, expand our mechanistic understanding of type II NPFs.

show abstract

“…Because the Arp2/3 complex plays a key role in nucleating actin filament branching, specific amino acid residues (ARG19, ARG22, and GLN113) in GMFB and the Arp2/3 complex that stabilize the interactions have been identified 28 and are located mainly in pocket 2 of the 3D structure of GMFB. Thus, we searched for small-molecule drug candidates targeting the binding site of GMFB with Arp2/3 via the protein‒ligand interface fingerprint (PLIF) and ChemDiv using computer virtual screening.…”

Section: Resultsmentioning

confidence: 99%

“…Based on the binding site between GMFB and Arp2/3 28 , computerized virtual screening for potential GMFB inhibitors was conducted by the TargetMol Chemicals Inc with the ChemDiv compound library. Biocore analysis was performed to determine the binding affinity between GMFB and candidate inhibitors by Chen Hongzhuan’s laboratory (Shanghai Jiaotong University).…”

Section: Methodsmentioning

confidence: 99%

Glia maturation factor beta deficiency protects against diabetic osteoporosis by suppressing osteoclast hyperactivity

Shi

et al. 2023

Exp Mol Med

View full text Add to dashboard Cite

Excessive osteoclast activation, which depends on dramatic changes in actin dynamics, causes osteoporosis (OP). The molecular mechanism of osteoclast activation in OP related to type 1 diabetes (T1D) remains unclear. Glia maturation factor beta (GMFB) is considered a growth and differentiation factor for both glia and neurons. Here, we demonstrated that Gmfb deficiency effectively ameliorated the phenotype of T1D-OP in rats by inhibiting osteoclast hyperactivity. In vitro assays showed that GMFB participated in osteoclast activation rather than proliferation. Gmfb deficiency did not affect osteoclast sealing zone (SZ) formation but effectively decreased the SZ area by decreasing actin depolymerization. When GMFB was overexpressed in Gmfb-deficient osteoclasts, the size of the SZ area was enlarged in a dose-dependent manner. Moreover, decreased actin depolymerization led to a decrease in nuclear G-actin, which activated MKL1/SRF-dependent gene transcription. We found that pro-osteoclastogenic factors (Mmp9 and Mmp14) were downregulated, while anti-osteoclastogenic factors (Cftr and Fhl2) were upregulated in Gmfb KO osteoclasts. A GMFB inhibitor, DS-30, targeting the binding site of GMFB and Arp2/3, was obtained. Biocore analysis revealed a high affinity between DS-30 and GMFB in a dose-dependent manner. As expected, DS-30 strongly suppressed osteoclast hyperactivity in vivo and in vitro. In conclusion, our work identified a new therapeutic strategy for T1D-OP treatment. The discovery of GMFB inhibitors will contribute to translational research on T1D-OP.

show abstract

Analysis of the interactions between GMF and Arp2/3 complex in two binding sites by molecular dynamics simulation

Cited by 10 publications

References 32 publications

GMF as an Actin Network Remodeling Factor

GMF as an Actin Network Remodeling Factor

Abp1 promotes Arp2/3 complex-dependent actin nucleation and stabilizes branch junctions by antagonizing GMF

Glia maturation factor beta deficiency protects against diabetic osteoporosis by suppressing osteoclast hyperactivity

Contact Info

Product

Resources

About