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

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.