For example, based on IPD-IMGT/HLA 3.23.0, the HLA assignment, A*02:01:01G, includes 52 alleles that share the nucleotide sequence of exons 2 and 3 but that differ in the DNA sequence of exon 1, exons 4–8 or the noncoding regions (introns, 5′ and 3′ untranslated regions (UTR)). While the majority of HLA allelic polymorphism alters the DNA sequence in the ARD-encoding exons, additional polymorphisms have been observed outside of this region in random individuals. Alleles sharing the nucleotide sequence in the ARD exons form the G allele groups alleles encoding HLA proteins sharing their polypeptide sequences in this region form P groups. It includes the α1 and α2 domains of class I proteins, specified by exons 2 and 3, and the α1 and β1 domains of the class II proteins, specified by exon 2 of the class II HLA genes. The ARD is the region of the HLA protein that binds an antigenic peptide and interacts with the antigen receptors of T lymphocytes and the natural killer cell immunoglobulin-like receptors. Matching uses high resolution typing assignments based on the sequences of exons encoding the HLA molecule’s antigen recognition domain (ARD). More recently, selection of a permissive HLA-DPB1 T cell epitope mismatch has been added to the optimal matching criteria. In hematopoietic stem cell transplantation (HCT), the optimal match for unrelated donor and recipient is based on HLA-A, -B, -C, -DRB1, and sometimes –DQB1, since these loci strongly impact survival. The impact of amino acid sequence variation caused by substitutions in exons outside ARD regions in D-R pairs will be difficult to assess in HCT outcome studies since these mismatches do not occur very frequently. The observed variation between donor and recipient usually involved a single nucleotide difference (88% of mismatches) 88% of the non-ARD exon variants impacted the amino acid sequence. Of the 4320 allele comparisons overall, only 17 allele pairs were mismatched for non-ARD exons, 41 for noncoding regions and 9 for ARD exons. Over 97% of alleles at each locus were matched for their nucleotide sequence outside of the ARD exons. Next generation DNA sequencing was used to characterize both HLA exons and introns for HLA-A, -B, -C alleles exons 2, 3 and the intervening intron for HLA-DRB1 and exons only for HLA-DQA1 and -DQB1. This study was designed to evaluate the frequency of variation outside the ARD in 10/10 (HLA-A, -B, -C, -DRB1, -DQB1) matched unrelated donor transplant pairs (n=360). The relevance of mismatching donor and recipient for HLA variation outside the ARD on hematopoietic stem cell transplantation (HCT) outcomes is unknown. Structural comparison of the uniporter GLUT1 with its bacterial homologue XylE, a proton-coupled xylose symporter, allows examination of the transport mechanisms of both passive facilitators and active transporters.ġ] State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.Traditional DNA-based typing focuses primarily on interrogating the exons of HLA genes that form the antigen recognition domain (ARD). Structure-based analysis of these mutations provides an insight into the alternating access mechanism of GLUT1 and other members of the sugar porter subfamily. This structure allows accurate mapping and potential mechanistic interpretation of disease-associated mutations in GLUT1. The full-length protein, which has a canonical major facilitator superfamily fold, is captured in an inward-open conformation. Here we report the crystal structure of human GLUT1 at 3.2 Å resolution. Despite decades of investigation, the structure of GLUT1 remains unknown. Dysfunctional mutations may lead to GLUT1 deficiency syndrome, whereas overexpression of GLUT1 is a prognostic indicator for cancer. The glucose transporter GLUT1 catalyses facilitative diffusion of glucose into erythrocytes and is responsible for glucose supply to the brain and other organs. Diversity, Equity, Inclusion, and Access.Biologically Interesting Molecule Reference Dictionary (BIRD).
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