Computational model predicts function of Rho-GTPase binding for plexin receptor GAP activity on Rap1b via dynamic...

Area of Science:

• Molecular Biology
• Cell Signaling
• Structural Biology

Background:

• Plexin-semaphorin signaling is crucial for cell migration, neuronal development, angiogenesis, and immune responses.
• Plexins directly bind active Rho- and Ras-family GTPases via intracellular domains, including Rho-GTPase binding and GTPase-activating protein (GAP) segments.
• The structural dynamics of plexin-GTPase interactions, especially with multiple GTPases, remain incompletely understood.

Purpose of the Study:

• To investigate the conformational dynamics and network alterations in plexin-B1 when bound to single versus multiple GTPases.
• To compare the binding stability and interaction networks of plexin-B1 with Rap1b (Ras), Rnd1 (Rho), and Rac1 (Rho) under different binding conditions.

Main Methods:

• Molecular dynamics simulations were performed on six distinct plexin-B1-GTPase bound systems.
• Analysis included conformational changes, network centralities, and interaction stability.
• Computational models were validated against experimental hydrogen-deuterium exchange mass spectrometry data.

Main Results:

• Plexin-B1 dynamics were more altered with Rac1 compared to Rnd1, depending on Rap1b binding to the GAP domain.
• Rnd1 showed stronger, more stable interactions with plexin-B1 without Rap1b, whereas Rac1 exhibited fewer, less stable connections.
• Network dynamics differed significantly when plexin-B1 was bound to both Ras and Rho-GTPases versus a single GTPase.

Conclusions:

• Computational models provide insights into the molecular mechanisms of plexin-GTPase interactions.
• Understanding these dynamics is key to deciphering complex GTPase signaling pathways.
• The findings align with experimental data, enhancing our comprehension of plexin-mediated cellular processes.