Structural insights into leishmanolysins encoded on chromosome 10 of Leishmania (Viannia) braziliensis

Abstract

BACKGROUND Leishmanolysins have been described as important parasite virulence factors because of their roles in the infection of promastigotes and resistance to host’s defenses. Leishmania (Viannia) braziliensis contains several leishmanolysin genes in its genome, especially in chromosome 10. However, the functional impact of such diversity is not understood, but may be attributed partially to the lack of structural data for proteins from this parasite.OBJECTIVES This works aims to compare leishmanolysin sequences from L. (V.) braziliensis and to understand how the diversity impacts in their structural and dynamic features.METHODS Leishmanolysin sequences were retrieved from GeneDB. Subsequently, 3D models were built using comparative modeling methods and their dynamical behavior was studied using molecular dynamic simulations.FINDINGS We identified three subgroups of leishmanolysins according to sequence variations. These differences directly affect the electrostatic properties of leishmanolysins and the geometry of their active sites. We identified two levels of structural heterogeneity that might be related to the ability of promastigotes to interact with a broad range of substrates.MAIN CONCLUSION Altogether, the structural plasticity of leishmanolysins may constitute an important evolutionary adaptation rarely explored when considering the virulence of L. (V.) braziliensis parasites.

Virulence factor RNA transcript expression in the Leishmania Viannia subgenus: influence of species, isolate source, and Leishmania RNA virus-1

“…( V .) braziliensis infection [18]. The host immune response may weigh heavily on the outcome of parasitic infection in addition to select virulence factors where host phosphatases such as serine threonine phosphatases (STPs) have been shown to regulate the outcome of Leishmania spp.…”

“…VFs endogenous to Leishmania spp. including molecular chaperones such as heat-shock proteins (HSPs), cysteine proteinases (CPB), leishmanolysins, phosphatases, and proteinases have been known to aid in the promastigote-amastigote transformation process and have certain immunomodulatory effects [4, 17, 18].…”

Leishmania braziliensis: Strain-Specific Modulation of Phagosome Maturation

“…In L. braziliensis, GP63 is present on chromosome 10 and strains isolated from different clinical manifestations from the same geographical region have conserved domains and display specific polymorphisms in their catalytic sites (Medina et al, 2016; Sutter et al, 2017; Quaresma et al, 2018). This variability could result in different virulence patterns and clinical outcomes.…”

Homology Modeling of Leishmanolysin (gp63) from Leishmania panamensis and Molecular Docking of Flavonoids

“…These results are within the range of 59−71% reported previously by Sutter et al for a variety of L. major leishmanolysin proteins coded by chromosome 10. 16 The HEXXHXXGXXH motif of the active site, typical of the zincdependent metalloproteinases, is highly conserved. There is an insertion of 62 residues between glycine and the third histidine in each of the proteins modeled for the Leishmania species, as reported by Yao et al 8 The position of the active site is highlighted with two of the histidines being part of the α-helix (H8) and the other in a loop in the central domain.…”