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Related Concept Videos

Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

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Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
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Rab Cascades01:25

Rab Cascades

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Rab GTPases act in a regulated cascade during membrane fusion, helping the lipid bilayers mix. The Rab family of proteins are active when bound to GTP, and inactive when bound to GDP. Hence, they act as guanine nucleotide-dependent molecular switches. Rab-GTP recognizes and binds to long or short-range tethering proteins to capture the target vesicle. These tethers coordinate with SNAREs on the vesicle and the target membrane to assemble the trans SNARE complex that locks the mixing bilayers.
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Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

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Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
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Rab Proteins01:14

Rab Proteins

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Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
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GTPases and their Regulation02:14

GTPases and their Regulation

8.3K
Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒  small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins,...
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IP3/DAG Signaling Pathway01:11

IP3/DAG Signaling Pathway

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Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
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Updated: Jun 14, 2025

Comparing the Affinity of GTPase-binding Proteins using Competition Assays
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Comparing the Affinity of GTPase-binding Proteins using Competition Assays

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Computation model predicts Rho GTPase function with the Plexin Transmembrane receptor GAP activity on Rap1b via

Nisha Bhattarai1, Lindsay Morrison2, Alexandre F Gomes2

  • 1Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA.

Biorxiv : the Preprint Server for Biology
|June 4, 2025
PubMed
Summary

Plexin-GTPase interactions were simulated, revealing Rac1 dynamics are more altered than Rnd1. Rnd1 shows stronger binding to Plexin-B1 without Rap1b, unlike Rac1, enhancing understanding of cell signaling.

Keywords:
GTPasesMolecular dynamics simulationsPlexinsStructural biologyhydrogen-deuteriummass spectroscopy

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Affinity Precipitation of Active Rho-GEFs Using a GST-tagged Mutant Rho Protein GST-RhoAG17A from Epithelial Cell Lysates
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Detection of Small GTPase Prenylation and GTP Binding Using Membrane Fractionation and GTPase-linked Immunosorbent Assay
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Detection of Small GTPase Prenylation and GTP Binding Using Membrane Fractionation and GTPase-linked Immunosorbent Assay
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Area of Science:

  • Molecular biology
  • Cell signaling
  • Biophysics

Background:

  • Plexin-semaphorin signaling is crucial for cell migration, neuronal development, and immune responses.
  • Plexins bind active Rho- and Ras-family GTPases via intracellular domains, including Rho-GTPase Binding Domains (RBD) and GTPase Activating Protein (GAP) segments.
  • The structural dynamics and conformational changes affecting plexin-GTPase interactions, especially with dual or single GTPase binding, remain unclear.

Purpose of the Study:

  • To investigate the conformational differences and dynamics of Plexin-B1 when bound to Rap1b, Rnd1, and Rac1 using molecular dynamics (MD) simulations.
  • To compare the network dynamics and interaction stability of plexin-GTPase complexes under varying binding conditions (dual vs. single GTPase).

Main Methods:

  • Conducted six distinct molecular dynamics (MD) simulations of plexin-GTPase bound systems.
  • Analyzed conformational changes, network centralities, and interaction stability.
  • Validated computational models against experimental hydrogen-deuterium exchange mass spectrometry (HDX-MS) data.

Main Results:

  • Rac1 dynamics showed greater alterations compared to Rnd1, influenced by the binding status of plexin's GAP domain with Rap1b.
  • Rnd1 demonstrated stronger and more stable interactions with Plexin-B1 in the absence of Rap1b.
  • Rac1 exhibited fewer and less stable connections with Plexin-B1 compared to Rnd1.
  • MD simulations broadly agreed with experimental HDX-MS findings.

Conclusions:

  • Computational models provide insights into the molecular mechanisms of Plexin-GTPase interactions.
  • Understanding these dynamics is key to deciphering complex GTPase-mediated signaling pathways.
  • The study highlights differential binding affinities and dynamic behaviors of GTPases with Plexin-B1.