Insights into the Effect of Lowe Syndrome-Causing Mutation p.Asn591Lys of OCRL‑1 through Protein–Protein Interaction Networks and Molecular Dynamics Simulations

• Published in: Journal of chemical information and modeling 2020-02, Vol.60 (2), p.1019-1027
• Main Authors: Acosta-Tapia, Natali, Galindo, Johan Fabian, Baldiris, Rosa
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Amino acids; Computer simulation; Endosomes; Functional analysis; Hydrogen Bonding; Localization; Molecular dynamics; Molecular Dynamics Simulation; Mutation; Oculocerebrorenal Syndrome - genetics; Phosphatase; Phosphoric Monoester Hydrolases - chemistry; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; Protein Conformation; Protein Interaction Mapping; Proteins; rab GTP-Binding Proteins - metabolism; Signal transduction; Thermodynamics; Variation
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.9b01077

Inositol polyphosphate 5-phosphatase (OCRL-1) participates in the regulation of multiple cellular processes, through the conversion of phosphatidylinositol 4,5-phosphate to phosphatidylinositol 4-phosphate. Mutations in this protein are related to Lowe syndrome (LS) and Dent-2 disease. In this study, the impact of Lowe syndrome mutations on the interactions of OCRL-1 with other proteins was evaluated through bioinformatic and computational approaches. In the functional analysis of the interaction network of the proteins, we found that the terms of gene ontology (GO) of greater significance were related to the intracellular transport of proteins, the signal transduction mediated by small G proteins and vesicles associated with the Golgi apparatus. From the proteins present in the GO terms of greater significance Rab8a was selected because its interaction facilitates the intracellular distribution of OCRL-1. The mutation p.Asn591Lys, present in the interaction domain of OCRL-1 and Rab8a, was studied using molecular dynamics. The molecular dynamics analysis showed that the presence of this mutation causes changes in the positional fluctuations of the amino acids and affects the flexibility of the protein making the interaction with Rab8a weaker. Rab proteins establish some specific interactions, which are important for the intracellular localization of OCRL-1; therefore, our findings suggest that the phenotype observed in patients with LS, in this case, is due to the destabilizing effect of p.Asn591Lys affecting the localization of OCRL-1 and indirectly its 5-phosphatase activity in the Golgi apparatus, endosomes, and cilia.