Hla-Dm Recognizes the Flexible Conformation of Major Histocompatibility Complex Class II

Chou, Chih Ling; Sadegh‐Nasseri, Scheherazade

doi:10.1084/jem.192.12.1697

Cited by 112 publications

(158 citation statements)

References 45 publications

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“…The association curve for DR1βH81N had a more prominent first phase, presumably because of the faster dissociation rate of existing peptide-DR1βH81N complexes (discussed below), which would result in an increased molar fraction of molecules in the peptide-receptive conformation during the association reaction. This result was in contrast to the kinetic pattern of the binding of peptide to DR1βG86Y, which is monophasic 25 , presumably because of the βG86Y substitution that fills pocket 1. That difference is important, as it demonstrated that the DR1βH81N mutant we generated, unlike DR1βG86Y, is not fixed in a peptide-receptive conformation.…”

Section: βH81n Does Not Alter the Biphasic Nature Of Peptide Bindingcontrasting

confidence: 50%

“…NIH-PA Author Manuscript NIH-PA Author Manuscript and the peptide 22,27,28 or to subtle structural variations among different peptide-MHC complexes 25,[29][30][31][32] , whereby structurally flexible complexes are susceptible to DM-induced dissociation, and `rigid' complexes are resistant to DM 25 . Although those studies may have brought greater understanding of the criteria for the recognition of specific peptide-MHC complexes by DM, the exact mechanism for DM effector function remains unknown.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

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HLA-DM targets the hydrogen bond between the histidine at position β81 and peptide to dissociate HLA-DR–peptide complexes

et al. 2006

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The peptide editor HLA-DM (DM) mediates exchange of peptides bound to major histocompatibility (MHC) class II molecules during antigen processing; however, the mechanism by which DM displaces peptides remains unclear. Here we generated a soluble mutant HLA-DR1 with a histidine-to-asparagine substitution at position 81 of the β-chain (DR1βH81N) to perturb an important hydrogen bond between MHC class II and peptide. Peptide-DR1βH81N complexes dissociated at rates similar to the dissociation rates of DM-induced peptide-wild-type DR1, and DM did not enhance the dissociation of peptide-DR1βH81N complexes. Reintroduction of an appropriate hydrogen bond (DR1βH81N βV85H) restored DM-mediated peptide dissociation. Thus, DR1βH81N might represent a `post-DM effect' conformation. We suggest that DM may mediate peptide dissociation by a `hit-and-run' mechanism that results in conformational changes in MHC class II molecules and disruption of hydrogen bonds between βHis81 and bound peptide.Shortly after being synthesized in the antigen-presenting cell, major histocompatibility complex (MHC) class II αβ heterodimers form nonameric assemblies with invariant chain (Ii) in the endoplasmic reticulum and are then transported through the Golgi complex to the endocytic pathway 1, 2. During transport through the endocytic pathway, most Ii is removed from MHC class II molecules by low pH and acid proteases3, leaving a proteolytic fragment of Ii called `CLIP' bound to MHC class II molecule4. CLIP acts as a `placeholder' for the MHC class II groove, inhibiting conformational changes that render the groove closed5 -13 , and it must be removed to allow binding of exogenous peptides to nascent MHC class II complexes. Human HLA-DM (called `DM' here), or H2-M in mice, is a nonclassical HLA molecule that is critical in the displacement of CLIP 14-17. In addition to displacing CLIP, DM transiently interacts with empty MHC class II molecules to generate a peptide-receptive conformation and is active in the selection of specific peptide-MHC class II complexes during antigen processing18 -26. The two concurrent hypotheses for the recognition of certain peptide-MHC class II by DM relate to the intrinsic affinity between MHC class II © 2006 Nature Publishing Group Correspondence should be addressed to S.S-N (ssadegh@jhmi.edu).. 4 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Immunology website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. NIH Public Access Author ManuscriptNat Immunol. Author manuscript; available in PMC 2011 January 12. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript and the peptide 22,27,28 or to subtle structural variations among different peptide-MHC complexes 25,[29][30][31][32] , whereby structurally flexible complexes are susceptible to DM-induced dissociation, and `rigid' complexes are resistant to DM 25 . Although those studies may have brought greater understanding of the crite...

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Section: βH81n Does Not Alter the Biphasic Nature Of Peptide Bindingcontrasting

confidence: 50%

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

HLA-DM targets the hydrogen bond between the histidine at position β81 and peptide to dissociate HLA-DR–peptide complexes

et al. 2006

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“…In the endocytic compartments, DM catalyzes the dissociation of CLIP, facilitating peptide loading onto class II molecules [18][19][20]. Because these events occur within the endocytic compartments, DM molecules should have little role in the presentation of CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide acquired on the cell surface.…”

Section: Discussionmentioning

confidence: 99%

“…The peptides that form stable complexes with class II proteins are displayed at the cell surface for recognition by CD4 + T cells. Additionally, studies suggest that DM molecules regulate epitope selection and T cell responses in the context of HLA class II molecules [20][21][22]. Thus, variations in DM expression within the thymus or in the periphery may regulate class II-restricted presentation of epitopes, potentially influencing the activation of autoreactive T cells.…”

Section: Introductionmentioning

confidence: 99%

“…The non-classical HLA, HLA-DM (DM), acts by catalyzing the removal of CLIP and subsequent capture of peptide epitopes by class II molecules [17,18]. The binding of peptide epitopes to class II proteins is selective, whether or not DM is present [18][19][20]. The peptides that form stable complexes with class II proteins are displayed at the cell surface for recognition by CD4 + T cells.…”

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HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

et al. 2008

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Rheumatoid arthritis, an autoimmune disease, is significantly associated with the HLA class II allele HLA-DR4. While the etiology of rheumatoid arthritis remains unknown, type II collagen (CII) is a candidate autoantigen. An immunodominant pathogenic epitope from this autoantigen, CII [261][262][263][264][265][266][267][268][269][270][271][272][273] , which binds to HLA-DR4 and activates CD4 + T cells, has been identified. The non-classical class II antigen, HLA-DM, is also a key component of class II antigen presentation pathways influencing peptide presentation by HLA-DR molecules expressed on professional antigen-presenting cells (APC). Here, we investigated whether the HLA-DR4-restricted presentation of the pathogenic CII 261-273 epitope was regulated by HLA-DM expression in APC. We show that APC lacking HLA-DM efficiently display the CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide/epitope to activate CD4 + T cells, and that presentation of this peptide is modulated dependent on the level of HLA-DM expression in APC. Mechanistic studies demonstrated that the CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide is internalized by APC and edited by HLA-DM molecules in the recycling pathway, inhibiting peptide presentation and T cell recognition. These findings suggest that HLA-DM expression in APC controls class IImediated CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide/epitope presentation and regulates CD4 + T cell responses to this self epitope, thus potentially influencing CII-dependent autoimmunity.Key words: CD4 + T cells Á HLA-DM Á HLA-DR Á Peptide presentation Á Type II collagen IntroductionType II collagen (CII) is the major protein component of articular cartilage [1]. It is thought that T and B cell responses to this autoantigen are associated with the development and pathogenesis of rheumatoid arthritis (RA) [2,3]. It is also widely believed that RA is genetically linked to HLA class II molecules, including some HLA-DR4 alleles, and that T cell responses in collagendependent RA are directed towards the immunodominant pathogenic epitope CII [261][262][263][264][265][266][267][268][269][270][271][272][273] [4,5]. Studies also suggest that T cells from patients with RA predominantly recognize the glycosylated form of the immunodominant CII peptide [6,7]. Professional antigen-presenting cells (APC) such as B cells, macrophages and dendritic cells abundantly express HLA class II proteins and play critical roles in the pathogenesis of autoimmune arthritis by presenting autoantigens to T cells [4,5,8].In RA, cartilage proteins including CII undergo degradation by proteases, leading to the generation of peptides that can bind to HLA class II proteins and trigger CD4 + T cell activation [9]. Studies suggest that the peptides are loaded onto class II proteins Eur. J. Immunol. 2008. 38: 1961-1970 Immunomodulation in the endosomal and lysosomal compartments of APC prior to transit to the cell surface for T cell recognition [5...

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Flexibility of the MHC class II peptide binding cleft in the bound, partially filled, and empty states: A molecular dynamics simulation study

2008

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Major histocompatibility (MHC) Class II cell surface proteins present antigenic peptides to the immune system. Class II structures in complex with peptides but not in the absence of peptide are known. Comparative molecular dynamics (MD) simulations of a Class II protein (HLA‐DR3) with and without CLIP (invariant chain‐associated protein) peptide were performed starting from the CLIP‐bound crystal structure. Depending on the protonation of acidic residues in the P6 peptide‐binding pocket the simulations stayed overall close to the start structure. The simulations without CLIP showed larger conformational fluctuations especially of α‐helices flanking the binding cleft. Largest fluctuations without CLIP were observed in a helical segment near the peptide C‐terminus binding region matching a segment recognized by antibodies specific for empty Class II proteins. Simulations on a Val86Tyr mutation that fills the peptide N‐terminus binding P1 pocket or of a complex with a CLIP fragment (dipeptide) bound to P1 showed an unexpected long range effect. In both simulations the mobility not only of P1 but also of the entire binding cleft was reduced compared to simulations without CLIP. It correlates with the experimental finding that the CLIP fragment binding to P1 is sufficient to prevent antibody recognition specific for the empty form at a site distant from P1. The results suggest a mechanism how a local binding event of small peptides or of an exchange factor near P1 may promote peptide binding and exchange through a long range stabilization of the whole binding cleft in a receptive (near bound) conformation. © 2008 Wiley Periodicals, Inc. Biopolymers 91: 14–27, 2009.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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Hla-Dm Recognizes the Flexible Conformation of Major Histocompatibility Complex Class II

Cited by 112 publications

References 45 publications

HLA-DM targets the hydrogen bond between the histidine at position β81 and peptide to dissociate HLA-DR–peptide complexes

HLA-DM targets the hydrogen bond between the histidine at position β81 and peptide to dissociate HLA-DR–peptide complexes

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

Flexibility of the MHC class II peptide binding cleft in the bound, partially filled, and empty states: A molecular dynamics simulation study

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