Dynamics of MHC-I molecules in the antigen processing and presentation pathway

Truong, Hau V.; Sgourakis, Nikolaos G.

doi:10.1016/j.coi.2021.04.012

Cited by 18 publications

(15 citation statements)

References 63 publications

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“…Measuring the k on separately from the k off requires an empty receptor, and since the binding site of empty wild type MHC‐I is natively unfolded and binds peptide only slowly (if at all), 19 , 20 , 21 , 22 , 23 , 24 , 25 we used empty disulfide‐stabilized MHC‐I (dsMHC‐I) molecules, which have a disulfide bond linking the α 1 and α 2 helices of the peptide‐binding groove, conformationally stabilizing the F pocket region in the absence of peptide in a structure that is close to the peptide‐bound state. 8 , 9 , 26 , 27 , 28 We first validated the use of dsA2 and dsA24 by repeating the exchange experiments, and we found that they exchange peptides significantly faster than their wild type (wt) counterparts and that they, importantly, show a similar dipeptide‐mediated and acidic acceleration of peptide exchange (Figure S1 ; Table S1 ).…”

Section: Resultsmentioning

confidence: 99%

Fast peptide exchange on major histocompatibility complex class I molecules by acidic stabilization of a peptide‐empty intermediate

et al. 2022

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The cell biology and biochemistry of peptide exchange on major histocompatibility complex class I (MHC‐I) proteins are of great interest in the study of immunodominance, which requires iterative optimization of peptide affinity, and cross‐presentation of pathogen and tumor antigens, in which endogenous peptides are exchanged for exogenous ones. Even though several methods exist to catalyze peptide exchange on recombinant MHC‐I proteins, the cellular conditions and mechanisms allowing for peptide exchange in vivo remain unclear. Here, we demonstrate that low pH, as present in endosomes, indeed triggers peptide exchange, and we dissect the individual steps of the exchange reaction. We find that low pH stabilizes the peptide‐empty forms of MHC‐I that occur as intermediates of the exchange reaction, and that is synergizes with dipeptides and with disulfide‐mediated stabilization of MHC‐I.

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Section: Resultsmentioning

confidence: 99%

Fast peptide exchange on major histocompatibility complex class I molecules by acidic stabilization of a peptide‐empty intermediate

et al. 2022

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“…Antigen processing and presentation is a fundamental pathway in vertebrates, in which the epitope peptides forming the intracellular proteome interact with MHC-I or MHC-II, to enable different aspects of adaptive immunity to emerge [ 37 , 38 ]. In this paper, 0.05 and 0.25 mg/mL BP5 immunization induced various DEG involved in antigen processing and presentation pathways, and also involved in antigen receptor-mediated signaling pathways and MHC class Ib receptor activity.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of spleen B cell revealed the molecular basis of bursopentin on B cell differentiation

Zhang

Cai

Hao

et al. 2022

Vet Res

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The bursa of Fabricius, the acknowledged humoral immune organ unique to birds, plays a vital role in B cell development. Bursopentin (BP5) derived from the bursa is reported to induce the development and formation of B cells. However, the mechanism of BP5 on B cell differentiation is still unclear. In this paper, total B lymphocytes from mice immunized with H9N2 subtype AIV vaccine were stimulated with BP5. The results show that BP5 at the experimental dosages promoted B cell differentiation, including the total B cells, activated B cells, differentiated B cells, mature B cells and plasma cells. Then, the in vivo immune experiment proved that the percentages of activated and differentiated B cells from mice immunized with AIV vaccine and 0.25 mg/mL BP5 were increased. To investigate the molecular mechanism of BP5 on B cell differentiation, the gene expression profiles of B cells purified from the spleen cells of mice immunized with AIV vaccine and BP5 were detected following RNA sequencing technology. The results show that BP5 at 0.05 and 0.25 mg/mL induced the enrichment of various biological functions, and stimulated five common significant enrichment pathways in B cells from the immunized mice. Additionally, 120 and 59 differentially expressed genes (DEG) represented transcriptional factors in B cells following 0.05 and 0.25 mg/mL BP5 immunization, respectively. In summary, these results suggest that BP5 regulates various gene expression involved in regulation of B cell development, which provides the knowledge required for additional studies on B cell differentiation in response to bursal-derived peptides and also provides an important experimental basis for improving vaccine immunity.

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“…As such, within the endoplasmic reticulum (ER), there is an elaborate network of specialized proteins, referred to as the peptide-loading complex (PLC) 6 , that ensures MHC I molecules are loaded with high-affinity peptides prior to their transport to the cell surface. Studies of the mechanism by which high-affinity peptides become ligands of MHC I have highlighted that the F pocket at the C-terminal end of the groove is a critical region of conformational sensing [7][8][9][10][11][12][13][14][15] . Indeed, the PLC proteins tapasin, ERp57, and calreticulin are spatially organized on MHC I molecules using sites of interaction at the C-terminal end of the groove 16 .…”

Section: Introductionmentioning

confidence: 99%

“…Molecular dynamic (MD) studies have suggested that the MHC I groove fluctuates rapidly between conformations, and it is the molecular features of such intermediate states that are recognized by specialized proteins, particularly tapasin [7][8][9][10][11][12][13][14][15] . The binding of tapasin to immature MHC I molecules induces a widening of the groove thereby encouraging the dissociation of nonoptimally bound peptides 17 .…”

Section: Introductionmentioning

confidence: 99%

Unusual crystal structures of MHC class I complexes reveal the elusive intermediate conformations explored during peptide editing in antigen presentation

Peng

Batliwala

et al. 2023

Preprint

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Studies have suggested that MHC class I (MHC I) molecules fluctuate rapidly between conformational states as they sample peptides for potential ligands. To date, MHC I intermediates are largely uncharacterized experimentally and remain elusive. We present x-ray crystal structures of HLA-B8 loaded with 20mer peptides that show significant conformational heterogeneity at the N-terminus of the groove. Long stretches of N-terminal residues were missing in the electron density maps creating an unstructured and widely open-ended groove. Our structures also revealed highly unusual features in MHC I and peptide conformations, and in MHC I-peptide interaction at the N-terminus of the groove. Molecular dynamics simulations showed that the complexes have varying degrees of flexibility in a manner consistent with the structures. We suggest that our structures represent transient substates explored by MHC I molecules during peptide editing. The visualization of peptide-dependent conformational flexibility in MHC I groove is a major step forward in our conceptual understanding of peptide repertoire development in antigen presentation. Our study also raises questions about the role of the N-terminus of the groove in peptide editing.

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Dynamics of MHC-I molecules in the antigen processing and presentation pathway

Cited by 18 publications

References 63 publications

Fast peptide exchange on major histocompatibility complex class I molecules by acidic stabilization of a peptide‐empty intermediate

Fast peptide exchange on major histocompatibility complex class I molecules by acidic stabilization of a peptide‐empty intermediate

Transcriptomic analysis of spleen B cell revealed the molecular basis of bursopentin on B cell differentiation

Unusual crystal structures of MHC class I complexes reveal the elusive intermediate conformations explored during peptide editing in antigen presentation

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