Abstract
Alsin is a protein of 1,657 amino acids known for its crucial role in vesicular trafficking in neurons thanks to its ability to interact with two guanosine triphosphatases, Rac1 and Rab5. Evidence suggests that Rac1 can bind Alsin central region, composed by a Dbl Homology (DH) domain followed by a Pleckstrin Homology (PH) domain, leading to Alsin relocalization. However, Alsin three-dimensional structure and its relationship with known biological functions of this protein are still unknown. In this work, a homology model of the Alsin DH/PH domain was developed and studied through molecular dynamics both in the presence and in the absence of its binding partner, Rac1. Due to different conformations of DH domain, the presence of Rac1 seems to stabilize an open state of the protein, while the absence of its binding partner results in closed conformations. Furthermore, Rac1 interaction was able to reduce the fluctuations in the second conserved region of DH motif, which may be involved in the formation of a homodimer. Moreover, the dynamics of DH/PH was described through a Markov State Model to study the pathways linking the open and closed states. In conclusion, this work provided an all-atom model for the DH/PH domain of Alsin protein; moreover, molecular dynamics investigations suggested underlying molecular mechanisms in the signal transduction between Rac1 and Alsin, providing the basis for a deeper understanding of the whole structure–function relationship for Alsin protein.
Highlights
Alsin is a protein of 1,657 amino acids encoded by the amyotrophic lateral sclerosis type 2 (ALS2) gene
For each template, the identity and similarity scores relative to Alsin were computed using Molecular Operating Environment (MOE) with the following procedure: the crystal structures of the templates were retrieved from Protein Data Bank, their sequences were aligned with one of the Alsin Dbl Homology (DH)/Pleckstrin Homology (PH) domain, the amino acids outside the region covered by Alsin residues were deleted, and the scores were computed by dividing the length of Alsin sequence
The homology model of Alsin DH/PH domain was built by I-Tasser using 16 templates
Summary
Alsin is a protein of 1,657 amino acids encoded by the amyotrophic lateral sclerosis type 2 (ALS2) gene. The knowledge of the molecular mechanisms underlying Alsin biological functions and the nanoscale effect of mutations is crucial to design potential therapeutic strategies. Before the release of the AlphaFold protein structure database (Jumper et al, 2021), RLD was the only domain that had been modeled (Soares et al, 2009; Sato et al, 2018), while none of the Alsin regions has been studied exploiting molecular dynamics (MD) tools. Given the fundamental role of this region in Alsin biological functions and its different role from one of the similar motifs, this study aims to exploit homology modeling tools to build an atomistic model of the Alsin DH/PH domain and characterize its dynamics, both alone and in the presence of Rac. The putative molecular mechanism underlying the signal transduction between Rac and Alsin will be reported
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