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

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.