Computational and atomistic studies applied to the understanding of the structural and behavioral features of the immune checkpoint HLA-G molecule and gene

Author(s)

Alves, Cinthia C. ; Arns, Thais ; Oliveira, Maria L. ; Moreau, Philippe ; Antunes, Dinler A. ; Castelli, Erick C. ; Mendes-Junior, Celso T. ; Giuliatti, Silvana ; Donadi, Eduardo A.

• Document type: Journal article
• Source: HUMAN IMMUNOLOGY; v. 84, n. 8, p. 10-pg., 2023-08-01.

Abstract

We took advantage of the increasingly evolving approaches for in silico studies concerning protein structures, protein molecular dynamics (MD), protein-protein and protein-DNA docking to evaluate: (i) the structure and MD characteristics of the HLA-G well-recognized isoforms, (ii) the impact of missense mutations at HLA-G receptor genes (LILRB1/2), and (iii) the differential binding of the hypoxia-inducible factor 1 (HIF1) to hypoxia-responsive elements (HRE) at the HLA-G gene. Besides reviewing these topics, they were revisited including the following novel results: (i) the HLA-G6 isoforms were unstable docked or not with & beta;2microglobulin or peptide, (ii) missense mutations at LILRB1/2 genes, exchanging amino acids at the intracellular domain, particularly those located within and around the ITIM motifs, may impact the HLA-G binding strength, and (iii) HREs motifs at the HLA-G promoter or exon 2 regions exhibiting a guanine at their third position present a higher affinity for HIF1 when compared to an adenine at the same position. These data shed some light into the functional aspects of HLA-G, particularly how polymorphisms may influence the role of the molecule. Computational and atomistic studies have provided alternative tools for experimental physical methodologies, which are time-consuming, expensive, demanding large quantities of purified proteins, and exhibit low output. (AU)

• FAPESP's process: 17/10780-4 - Effect of CRISPR-Cas9-induced mutations in the Aire gene (APS1 syndrome) on protein conformation, mTEC cell transcriptome and their interaction with thymocytes
• Grantee: Geraldo Aleixo da Silva Passos Júnior
• Support Opportunities: Research Projects - Thematic Grants