Transmembrane Domain-Mediated Colocalization of HLA-DM and HLA-DR Is Required for Optimal HLA-DM Catalytic Activity

Weber, Dominique A.; Dao, Chinh T.; Jun, Julie; Wigal, Jerrod L.; Jensen, Peter E.

doi:10.4049/jimmunol.167.9.5167

Cited by 31 publications

(27 citation statements)

References 51 publications

(77 reference statements)

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“…The Ii chain has also been shown to weakly interact with conventional class II transmembrane domains, and these contacts depend on detergent and isolation conditions (54,114,115). Interestingly, DM transmembrane/cytoplasmic domains are known to contribute to its peptide editing functions (116). Perhaps Ii chain also associates with DM via its transmembrane and/or cytoplasmic segments.…”

Section: Discussionmentioning

confidence: 99%

Dissecting MHC Class II Export, B Cell Maturation, and DM Stability Defects in Invariant Chain Mutant Mice

Koonce

Bikoff

2004

The Journal of Immunology

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Invariant (Ii) chain loss causes defective class II export, B cell maturation, and reduced DM stability. In this study, we compare Ii chain and class II mutant mouse phenotypes to dissect these disturbances. The present results demonstrate that ER retention of αβ complexes, and not β-chain aggregates, disrupts B cell development. In contrast, we fail to detect class II aggregates in Ii chain mutant thymi. Ii chain loss in NOD mice leads to defective class II export and formation of αβ aggregates, but in this background, downstream signals are misregulated and mature B cells develop normally. Finally, Ii chain mutant strains all display reduced levels of DM, but mice expressing either p31 or p41 alone, and class II single chain mutants, are indistinguishable from wild type. We conclude that Ii chain contributions as a DM chaperone are independent of its role during class II export. This Ii chain/DM partnership favors class II peptide loading via conventional pathway(s).

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Section: Discussionmentioning

confidence: 99%

Dissecting MHC Class II Export, B Cell Maturation, and DM Stability Defects in Invariant Chain Mutant Mice

Koonce

Bikoff

2004

The Journal of Immunology

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“…DM was present at different concentrations (150 nM to 5 M) during photocleavage (10 min, 160 nM DR2-MBP-P4*), and MBP-488 was added (330 nM) after photocleavage. Saturation was not observed because of the lower affinity of soluble DM for soluble DR compared with full-length molecules (42).…”

Section: The Contribution Of Dm To Peptide Association Is Not Due To mentioning

confidence: 99%

Empty Class II Major Histocompatibility Complex Created by Peptide Photolysis Establishes the Role of DM in Peptide Association

Grotenbreg

Nicholson

Fowler³

et al. 2007

Journal of Biological Chemistry

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DM catalyzes the exchange of peptides bound to Class II major histocompatibility complex (MHC) molecules. Because the dissociation and association components of the overall reaction are difficult to separate, a detailed mechanism of DM catalysis has long resisted elucidation. UV irradiation of DR molecules loaded with a photocleavable peptide (caged Class II MHC molecules) enabled synchronous and verifiable evacuation of the peptide-binding groove and tracking of early binding events in real time by fluorescence polarization. Empty DR molecules generated by photocleavage rapidly bound peptide but quickly resolved into species with substantially slower binding kinetics. DM formed a complex with empty DR molecules that bound peptide with even faster kinetics than empty DR molecules just having lost their peptide cargo. Mathematical models demonstrate that the peptide association rate of DR molecules is substantially higher in the presence of DM. We therefore unequivocally establish that DM contributes directly to peptide association through formation of a peptide-loading complex between DM and empty Class II MHC. This complex rapidly acquires a peptide analogous to the MHC class I peptide-loading complex.Major histocompatibility complex (MHC) 5 molecules are cell surface proteins that present peptides to antigen-specific receptors on T cells. The Class II MHC products are specialized in sampling endosomal compartments to acquire these peptides. Delivery of newly synthesized and assembled Class II MHC proteins to endo-lysosomal compartments is assured by means of the transient association of the MHC ␣␤ heterodimer with the invariant chain, a protein endowed with both chaperone function and an address code (1, 2). In endosomal compartments, the invariant chain is destroyed, yielding a Class II MHC product occupied with an invariant chain-derived remnant, the CLIP peptide (3-5). The HLA-DM (DM) molecule, itself incapable of binding peptide, facilitates replacement of CLIP with antigenic peptides (6 -10). The action of DM is not limited to the Class II MHC/CLIP complex and extends to Class II MHCpeptide complexes more generally. Such editing by DM favors presentation to CD4 T cells of those peptides that are most resistant to peptide displacement by DM (9,(11)(12)(13)(14)(15)(16)(17).DM is a membrane-anchored heterodimer that belongs to the extended family of proteins with a MHC fold but lacks a functional peptide-binding groove (18,19). Mutagenesis experiments identified lateral surfaces on DM and DR molecules that are involved in the interaction between the two proteins. On the DR side, these mutations span the entire length of the ectodomain and are localized to the ␣1 and ␤2 domains (20). On the DM side, an extended interaction surface has been mapped that also spans the entire length of the ectodomain (21). These data support a model in which lateral interactions between DM and DR molecules induce a conformational change that destabilizes the DR-bound peptide. It has been proposed that DM disrupts one or severa...

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“…[16][17][18][19][20] DM and DR interact principally in acidic vesicles and membrane colocalization increases the efficiency of peptide exchange. 21 The mutual recognition would involve fine structural changes in both molecules. A DMsusceptible, flexible isoform of DR may arise from changes induced by inadequate peptides and from protonation of histidine a33 at low pH.…”

Section: Introductionmentioning

confidence: 99%

Evidence for a human leucocyte antigen‐DM‐induced structural change in human leucocyte antigen‐DOβ

et al. 2009

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SummaryHuman leucocyte antigen (HLA)-DO is a non-classical major histocompatibility complex class II molecule which modulates the function of HLA-DM and the loading of antigenic peptides on molecules such as HLA-DR. The bulk of HLA-DO associates with HLA-DM and this interaction is critical for HLA-DO egress from the endoplasmic reticulum. HLA-DM assists the early steps of HLA-DO maturation presumably through the stabilization of the interactions between the N-terminal regions of the a and b chains. To evaluate a possible role for HLA-DM in influencing the conformation of HLA-DO, we made use of a monoclonal antibody, Mags.DO5, that was raised against HLA-DO/DM complexes. Using transfected cells expressing mismatched heterodimers between HLA-DR and -DO chains, we found that the epitope for Mags.DO5 is located on the DOb chain and that Mags.DO5 reactivity was increased upon cotransfection with HLA-DM. Our results suggest that HLA-DM influences the folding of HLA-DO in the endoplasmic reticulum. A mutant HLA-DO showing reduced capacity for endoplasmic reticulum egress was better recognized by Mags.DO5 in the presence of HLA-DM. On the other hand, an HLA-DO mutant capable of endoplasmic reticulum egress on its own was efficiently recognized by Mags.DO5, irrespective of the presence of HLA-DM. Taken together, our results suggest that HLA-DM acts as a private chaperone, directly assisting the folding of HLA-DO to promote egress from the endoplasmic reticulum.

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Transmembrane Domain-Mediated Colocalization of HLA-DM and HLA-DR Is Required for Optimal HLA-DM Catalytic Activity

Cited by 31 publications

References 51 publications

Dissecting MHC Class II Export, B Cell Maturation, and DM Stability Defects in Invariant Chain Mutant Mice

Dissecting MHC Class II Export, B Cell Maturation, and DM Stability Defects in Invariant Chain Mutant Mice

Empty Class II Major Histocompatibility Complex Created by Peptide Photolysis Establishes the Role of DM in Peptide Association

Evidence for a human leucocyte antigen‐DM‐induced structural change in human leucocyte antigen‐DOβ

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