Crystal Structure of HLA-DR2 (DRA*0101, DRB1*1501) Complexed with a Peptide from Human Myelin Basic Protein

Smith, Kathrine J.; Pyrdol, Jason W.; Gauthier, Laurent; Wiley, Don C.; Wucherpfennig, Kai W.

doi:10.1084/jem.188.8.1511

Cited by 280 publications

(270 citation statements)

References 59 publications

(92 reference statements)

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“…HLA-DR15 molecules derived from DRB1*1502 differ from those derived from DRB1*1501 in only one amino acid at position 86 (valine for DRB1*1502 and glycine for DRB1*1501) of the beta-chain [31]. This structural similarity indicates that antigenic epitopes presented by these molecules are common [32,33]. For most autoimmune diseases where DRB1*1501 is associated with susceptibility in patients from Western countries, DRB1*1502 is expected to play the same role as DRB1*1501 in Japanese patients.…”

Section: Discussionmentioning

confidence: 81%

Roles of DRB1∗1501 and DRB1∗1502 in the pathogenesis of aplastic anemia

Sugimori

Yamazaki

Feng

et al. 2007

Experimental Hematology

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Category Clinical investigations Word countsTotal text word count: 3412 words Abstract word count: 240 words 2 ABSTRACTObjective. Although a number of reports have documented a significantly increased incidence of HLA-DR15 in aplastic anemia (AA), the exact role of HLA-DR15 in the immune mechanisms of AA remains unclear. We herein clarify the difference between DRB1*1501 and DRB1*1502, the 2 DRB1 alleles which determine the presentation of HLA-DR15, in the pathophysiology of AA. Materials and Methods.We investigated the relationships of the patients' HLA-DRB1 allele with both the presence of a small population of CD55 -CD59 -(PNH-type) blood cells and the response to antithymocyte globulin (ATG) plus cyclosporine (CsA) therapy in 140 Japanese AA patients. Results. Of the 30 different DRB1 alleles, only DRB1*1501 (33.6% vs. 12.8%, P c <0.01) and DRB1*1502 (43.6% vs. 24.4%, P c <0.01) displayed significantly higher frequencies among the AA patients than among a control. AA patients possessing HLA-DR15 tended to be old, and especially, the frequency of DRB1*1502 in patients ≥40 years old (52.4%) was markedly higher than that in those <40 years old (16.2%, P c <0.01). Only DRB1*1501 was significantly associated with the presence of a small population of PNH-type cells and it also showed a good response to ATG plus CsA therapy in a univariate analysis. A multivariate analysis showed only the presence of a small population of PNH-type cells to be a significant factor associated with a good response to the immunosuppressive therapy (P<0.01). Conclusion.Although both DRB1*1501 and DRB1*1502 contribute to the development of AA, the methods of contribution differ between the two alleles.3

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Section: Discussionmentioning

confidence: 81%

Roles of DRB1∗1501 and DRB1∗1502 in the pathogenesis of aplastic anemia

Sugimori

Yamazaki

Feng

et al. 2007

Experimental Hematology

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“…In nearly all MHCII structures the p7 amino acid points laterally toward the ␤-chain ␣-helix. In some cases, its contribution to MHC interaction is minimal because of a small side chain (12)(13)(14)23) or a rotamer that brings the side chain to the surface (12,16,20,21). In a few cases, the p7 rotamer buries a portion of the side chain with considerable ␤-chain interaction (11,15,17,18).…”

Section: Resultsmentioning

confidence: 99%

Alternate interactions define the binding of peptides to the MHC molecule IA^b

Liu

Dai

Crawford

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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T he crystal structures of a variety of MHCI (1-9) and MHCII (10-23) molecules have revealed their features that lead to stable peptide binding. Conserved amino acids of MHCI interact with the N terminus and C terminus of the peptide in virtually all isotypes and alleles. Between these termini, the peptide can vary in length and in the path it takes through the binding groove, often bulging out of the groove in the middle. In MHCII, the N and C termini of the peptide generally extend beyond the binding groove and do not interact with the MHCII molecule. Rather, H-bonding interactions between the peptide backbone and conserved amino acids of the MHCII ␣-helices force the peptide to take a similar, extended path through the groove of all MHCII isotypes and alleles.The unique interactions that determine the allelic specificity of peptide binding seem to be controlled by the character of pockets within the interior of the binding groove that preferentially accept particular amino acid side chains. Because the MHC amino acids that line these pockets are among the most genetically variable, their depth, shape, and chemistry vary considerably among MHC alleles and isotypes, and they appear to be the most important factor in the specificity of peptide binding.In the current study we have solved the crystal structure of the mouse MHCII molecule IA b with a bound immunogenic peptide variant of a dominant peptide derived from the MHCII E␣ protein that is found in IA b in some strains of mice (24). Despite the high stability and immunogenicity of this complex, the four usual p1, p4, p6, and p9 peptide side chain binding pockets of IA b are largely unfilled, because alanines occur in the peptide at these positions. Rather, the stability of this peptide͞MHCII complex can be attributed to the combination of the conserved interactions with the peptide backbone as well as extensive unique interactions of the IA b molecule with other peptide amino acids particularly at the N-terminal end and the p7 position of the peptide. These results suggest that IA b can achieve stable peptide binding in more than one way and may account for the previous difficulty in defining the IA b peptidebinding motif. Materials and MethodsPreparation of Soluble IA b . The production of soluble IA b containing a peptide attached to the ␤-chain N terminus via a flexible peptide linker has been described (25). In the original constructions, peptides included both the E␣-derived peptide, ASFEAQGALANIAVDKA (pE␣), which occupies about 10% of natural IA b , and an immunogenic variant, ASFEAQKAK-ANKAVDKA (p3K), in which three positions in the peptide (underlined) had lysines substituted for the E␣ peptide amino acids. For crystallization, the construct was altered to use a shortened form of p3K, FEAKGAKANKAVD, and to shorten the IA b ␣ and ␤ chains to the predicted ends of the ␣2 and ␤2 domains. The construct was cloned into a previously described dual promoter baculovirus transfer vector (26, 27) and introduced into BacVector 3000 version of AcNPV baculovirus ...

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“…In a solution circular dichroism (CD) and Fourier transform infrared spectroscopic study, MBP peptides from this region were found to have both ␣-helix and ␤-sheet structures in methanol, with the latter increasing in amount in progressively shorter peptides (17). The crystal structures of peptides 85-99 and 86 -105 bound to class II MHC proteins have been found to be extended (18,19).We have previously used site-directed spin labeling (SDSL) and electron paramagnetic resonance (EPR) spectroscopy (20,21) to compare the membrane interactions of normal murine MBP (mMBP) with that of a less cationic form that predominates in MS (22). In that study, H85R1 was found to be motionally restricted, yet situated more than 3 Å above the lipid phosphate groups.…”

mentioning

confidence: 99%

An Immunodominant Epitope of Myelin Basic Protein Is an Amphipathic α-Helix

Bates

Feix

Boggs

et al. 2004

Journal of Biological Chemistry

124

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Myelin basic protein is a candidate autoantigen in multiple sclerosis. One of its dominant antigenic epitopes is segment Pro 85 to Pro 96 (human sequence numbering, corresponding to Pro 82 to Pro 93 in the mouse). There have been several, contradictory predictions of secondary structure in this region; either ␤-sheet, ␣-helix, random coil, or combinations thereof have all been proposed. In this paper, molecular dynamics and site-directed spin labeling in aqueous solution indicate that this segment forms a transient ␣-helix, which is stabilized in 30% trifluoroethanol. When bound to a myelin-like membrane surface, this antigenic segment exhibits a depth profile that is characteristic of an amphipathic ␣-helix, penetrating up to 12 Å into the bilayer. The ␣-helix is tilted ϳ9°, and the central lysine is in an ideal snorkeling position for side-chain interaction with the negatively charged phospholipid head groups.Multiple sclerosis (MS) 1 is thought to be an autoimmune disease characterized by chronic inflammatory response against myelin in the central nervous system. There is significant evidence that myelin basic protein (MBP) is a candidate antigen for T-cells and autoantibodies in MS (1). The 18.5-kDa isoform of MBP maintains the compaction of the myelin sheath in the central nervous system by anchoring the cytoplasmic face of the two apposing bilayers (2, 3). The mechanism and sites that are important for membrane adhesion are not known.The level of anti-MBP antibodies is increased in the cerebrospinal fluid of patients with active MS (4), as well as in 96% of patients with relapsing and chronic MS (5). An MBP region between Pro 85 and Pro 96 (human sequence numbering) was identified to be a minimal B cell epitope and a T cell epitope for HLA DR2b (DRB1*1501)-restricted T cells that recognize the protein (1, 6). This epitope overlaps with the DR2a-restricted epitope for T-cells reactive to MBP residues 87-106 (7). Experimental treatments for MS based on peptide mimetics of MBP have focused on this region of the protein (8).In solution, MBP is "intrinsically unstructured" (or "natively unfolded") (9). Upon binding to detergents or lipids, the levels of ␤-sheet and especially ␣-helical structure increase dramatically (10, 11). Presently the tertiary structure of MBP is unknown, with the most detailed predictions coming from Martenson (12) and Stoner (13) in the mid-1980s. In these models, as well as in a newer model based upon further research on an electron microscopy single-particle reconstruction, residues 86 -92 are found in a ␤-sheet (14, 15). Using [ 1 H]NMR and circular dichroic spectropolarimetry of various MBP peptides with detergent micelles, Mendz et al. (16) suggested that there were discrete interaction sites in the protein, one of which could be a helix between residues 87 and 97. Based on the arrangement of hydrophobic and hydrophilic residues, Warren et al. (6) predicted that this epitope of MBP was an amphipathic ␣-helix located at the interface between the oligodendrocyte cytoplasm and the me...

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Crystal Structure of HLA-DR2 (DRA0101, DRB11501) Complexed with a Peptide from Human Myelin Basic Protein

Cited by 280 publications

References 59 publications

Roles of DRB1∗1501 and DRB1∗1502 in the pathogenesis of aplastic anemia

Roles of DRB1∗1501 and DRB1∗1502 in the pathogenesis of aplastic anemia

Alternate interactions define the binding of peptides to the MHC molecule IA^b

An Immunodominant Epitope of Myelin Basic Protein Is an Amphipathic α-Helix

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Crystal Structure of HLA-DR2 (DRA*0101, DRB1*1501) Complexed with a Peptide from Human Myelin Basic Protein

Cited by 280 publications

References 59 publications

Roles of DRB1∗1501 and DRB1∗1502 in the pathogenesis of aplastic anemia

Roles of DRB1∗1501 and DRB1∗1502 in the pathogenesis of aplastic anemia

Alternate interactions define the binding of peptides to the MHC molecule IAb

An Immunodominant Epitope of Myelin Basic Protein Is an Amphipathic α-Helix

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Crystal Structure of HLA-DR2 (DRA0101, DRB11501) Complexed with a Peptide from Human Myelin Basic Protein

Alternate interactions define the binding of peptides to the MHC molecule IA^b