Abstract
HLA-G is considered to be an immune checkpoint molecule, a function that is closely linked to the structure and dynamics of the different HLA-G isoforms. Unfortunately, little is known about the structure and dynamics of these isoforms. For instance, there are only seven crystal structures of HLA-G molecules, being all related to a single isoform, and in some cases lacking important residues associated to the interaction with leukocyte receptors. In addition, they lack information on the dynamics of both membrane-bound HLA-G forms, and soluble forms. We took advantage of in silico strategies to disclose the dynamic behavior of selected HLA-G forms, including the membrane-bound HLA-G1 molecule, soluble HLA-G1 dimer, and HLA-G5 isoform. Both the membrane-bound HLA-G1 molecule and the soluble HLA-G1 dimer were quite stable. Residues involved in the interaction with ILT2 and ILT4 receptors (α3 domain) were very close to the lipid bilayer in the complete HLA-G1 molecule, which might limit accessibility. On the other hand, these residues can be completely exposed in the soluble HLA-G1 dimer, due to the free rotation of the disulfide bridge (Cys42/Cys42). In fact, we speculate that this free rotation of each protomer (i.e., the chains composing the dimer) could enable alternative binding modes for ILT2/ILT4 receptors, which in turn could be associated with greater affinity of the soluble HLA-G1 dimer. Structural analysis of the HLA-G5 isoform demonstrated higher stability for the complex containing the peptide and coupled β2-microglobulin, while structures lacking such domains were significantly unstable. This study reports for the first time structural conformations for the HLA-G5 isoform and the dynamic behavior of HLA-G1 molecules under simulated biological conditions. All modeled structures were made available through GitHub (https://github.com/KavrakiLab/), enabling their use as templates for modeling other alleles and isoforms, as well as for other computational analyses to investigate key molecular interactions.
Highlights
The Human Leukocyte Antigen G (HLA-G) is a nonclassical Major Histocompatibility Complex class I (MHC-I) molecule that possesses immunomodulatory properties [1]
The complete membrane-bound HLA-G1 model was applied as template for three possible HLA-G5 isoform structures: monomer, monomer containing the nonapeptide in the cleft, and monomer containing the nonapeptide in the cleft coupled to b2-microglobulin
The HLA-G5 monomer dynamic system contained 90,375 water molecules and 187 counter-ions; the monomer containing the nonapeptide in the cleft system had 90,135 water molecules and 185 counter-ions; and the monomer containing the nonapeptide in the cleft coupled to b2-microglobulin had 83,676 water molecules and 179 counter-ions
Summary
The Human Leukocyte Antigen G (HLA-G) is a nonclassical Major Histocompatibility Complex class I (MHC-I) molecule that possesses immunomodulatory properties [1]. ILT4 is myeloid-specific and only expressed by monocytes/dendritic cells [16], being capable of recognizing HLA-G free heavy chains [17, 18]. Through these differentially expressed receptors, HLA-G can interact with all these different cell types, primarily inhibiting their functions. The 5’ region of the intron, in the reading phase with exon 4, is translated into a stop codon and generates the HLA-G5 and HLA-G6 isoforms These isoforms contain a specific 21 residues long tail involved in molecule solubility. All alternative transcripts are devoid of exon 7 [26, 27]
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