Structural Requirements for Binding of Myelin Basic Protein (MBP) Peptides to MHC II: Effects on Immune Regulation

Mantzourani, Efi; Mavromoustakos, Thomas; Platts, James Alexis; Matsoukas, John; Tselios, Theodore

doi:10.2174/0929867054039053

Cited by 31 publications

(39 citation statements)

References 68 publications

(141 reference statements)

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“…This may also explain their antagonistic versus agonistic activity. Such differences in the binding motifs between linear and cyclic agonists and antagonists analogues of MBP 87-99 epitope were also shown in our previous work [19][20][21][22][23][24][25][26].…”

Section: Resultssupporting

confidence: 83%

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Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

Potamitis

Matsoukas

Tselios

et al. 2011

J Comput Aided Mol Des

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The two new synthetic analogues of the MBP(83-99) epitope substituted at Lys(91) (primary TCR contact) with Phe [MBP(83-99) (Phe(91))] or Tyr [MBP(83-99) (Tyr(91))], have been structurally elucidated using 1D and 2D high resolution NMR studies. The conformational analysis of the two altered peptide ligands (APLs) has been performed and showed that they adopt a linear and extended conformation which is in agreement with the structural requirements of the peptides that interact with the HLA-DR2 and TCR receptors. In addition, Molecular Dynamics (MD) simulations of the two analogues in complex with HLA-DR2 (DRA, DRB1*1501) and TCR were performed. Similarities and differences of the binding motif of the two analogues were observed which provide a possible explanation of their biological activity. Their differences in the binding mode in comparison with the MBP(83-99) epitope may also explain their antagonistic versus agonistic activity. The obtained results clearly indicate that substitutions in crucial amino acids (TCR contacts) in combination with the specific conformational characteristics of the MBP(83-99) immunodominant epitope lead to an alteration of their biological activity. These results make the rational drug design intriguing since the biological activity is very sensitive to the substitution and conformation of the mutated MBP epitopes.

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Section: Resultssupporting

confidence: 83%

“…NMR spectroscopy is coupled with MD simulations to study the binding motif of the altered peptide epitopes of MBP 83-99 with HLA-DR2 [19][20][21][22][23][24][25][26][27][28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

Potamitis

Matsoukas

Tselios

et al. 2011

J Comput Aided Mol Des

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“…One of the candidate autoantigens in MS is MBP, because of its early identification as an agent that can induce EAE in a susceptible host [235]. The cerebrospinal fluid of patients with MS contains both MBP-derived peptides [236] and elevated levels of autoantibodies to MBP [237][238][239][240][241][242][243], inspiring strategies for MS immunotherapy by injection of synthetic MBP peptides [243][244][245][246].…”

Section: Effects Of Deimination-mbp Immunogenicitymentioning

confidence: 99%

A Tale of Two Citrullines—Structural and Functional Aspects of Myelin Basic Protein Deimination in Health and Disease

2006

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Myelin basic protein (MBP) binds to negatively charged lipids on the cytosolic surface of oligodendrocyte membranes and is responsible for adhesion of these surfaces in the multilayered myelin sheath. The pattern of extensive post-translational modifications of MBP is dynamic during normal central nervous system (CNS) development and during myelin degeneration in multiple sclerosis (MS), affecting its interactions with the myelin membranes and with other molecules. In particular, the degree of deimination (or citrullination) of MBP is correlated with the severity of MS, and may represent a primary defect that precedes neurodegeneration due to autoimmune attack. That the degree of MBP deimination is also high in early CNS development indicates that this modification plays major physiological roles in myelin assembly. In this review, we describe the structural and functional consequences of MBP deimination in healthy and diseased myelin.

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“…Moreover, the intramolecular hydrogen bonds between the Gln 3 and Arg 5 (Fig. 7) for the [20,[26][27][28][29][30].…”

Section: Resultsmentioning

confidence: 99%

Conformational studies of immunodominant myelin basic protein 1–11 analogues using NMR and molecular modeling

Laimou

Lazoura

Troganis

et al. 2011

J Comput Aided Mol Des

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Τwo dimensional nuclear magnetic resonance studies complimented by molecular dynamics simulations were conducted to investigate the conformation of the immunodominant epitope of acetylated myelin basic protein residues 1-11 (Ac-MBP(1-11)) and its altered peptide ligands, mutated at position 4 to an alanine (Ac-MBP(1-11)[4A]) or a tyrosine residue (Ac-MBP(1-11)[4Y]). Conformational analysis of the three analogues indicated that they adopt an extended conformation in DMSO solution as no long distance NOE connectivities were observed and seem to have a similar conformation when bound to the active site of the major histocompatibility complex (MHC II). The interaction of each peptide with MHC class II I-A(u) was further investigated in order to explore the molecular mechanism of experimental autoimmune encephalomyelitis induction/inhibition in mice. The present findings indicate that the Gln(3) residue, which serves as a T-cell receptor (TCR) contact site in the TCR/peptide/I-A(u) complex, has a different orientation in the mutated analogues especially in the Ac-MBP(1-11)[4A] peptide. In particular the side chain of Gln(3) is not solvent exposed as for the native Ac-MBP(1-11) and it is not available for interaction with the TCR.

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Structural Requirements for Binding of Myelin Basic Protein (MBP) Peptides to MHC II: Effects on Immune Regulation

Cited by 31 publications

References 68 publications

Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

A Tale of Two Citrullines—Structural and Functional Aspects of Myelin Basic Protein Deimination in Health and Disease

Conformational studies of immunodominant myelin basic protein 1–11 analogues using NMR and molecular modeling

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