Phosphorylation of Ser111 in Rab8a Modulates Rabin8-Dependent Activation by Perturbation of Side Chain Interaction Networks

Biochemistry
Danial Pourjafar-DehkordiMartin Zacharias

Abstract

GTPases are key players during cellular signaling. Phosphorylation of Rab proteins, which belong to the Ras superfamily of small GTPases regulating intracellular transport, has been implicated in the pathogenesis of Parkinson's disease. For Rab8a, it was shown that serine 111 phosphorylation (pS111) is dependent on the protein kinase PINK1 and that mimicking the phosphorylation at S111 by a serine/glutamate substitution (S111E) impaired Rab8a activation by its cognate nucleotide exchange factor (GEF) Rabin8. However, Ser111 is not part of the interface of the Rab8a:Rabin8 complex. Here, we performed comparative molecular dynamics and free energy simulations on Rab8a and Rab8a:Rabin8 complexes to elucidate the molecular details of how pS111 and S111E may influence the interaction with Rabin8. The simulations indicate that S111E and pS111 establish an intramolecular interaction with arginine 79 (R79). The interaction persists in the complex and perturbs a favorable intermolecular salt-bridge contact between R79 in Rab8a and aspartate 187 in Rabin8. Binding free energy analysis reveals that S111E and pS111, as well as the R79A mutation, drastically decrease the binding affinity for Rabin8. Combining the R79A mutation with S111E or...Continue Reading

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Citations

Aug 5, 2020·Annual Review of Cell and Developmental Biology·Pawan Kishor Singh, Miratul M K Muqit
Apr 23, 2021·Biophysical Journal·Dieter WaschbüschAmir R Khan
May 4, 2021·Movement Disorders : Official Journal of the Movement Disorder Society·David J KossTiago F Outeiro
Aug 31, 2021·Frontiers in Molecular Biosciences·Edward KingRay Luo

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