Zinc-binding Sites in the N Terminus of Mycoplasma arthritidis-derived Mitogen Permit the Dimer Formation Required for High Affinity Binding to HLA-DR and for T Cell Activation

Langlois, Marc‐André; Fakhry, Youssef El; Mourad, Walid

doi:10.1074/jbc.m300823200

Cited by 13 publications

(15 citation statements)

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“…It is well established that metal ions, Zn 2+ in particular, play an important role in the biological function of certain SAgs (Etongue-Mayer et al, 2002;Hudson et al, 1995;Kozono et al, 1995;Langlois et al, 2003;Li et al, 1999Li et al, , 2001. Zinc may regulate the SAg activity in several ways.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies suggested that MAM superantigenic activity is Zn 2+ dependent (Bernatchez et al, 1997;Driessen et al, 1995;Etongue-Mayer et al, 2002;Langlois et al, 2003). MAM can induce cytokine gene expression on a human monocytic cell line, THP-1 (Bernatchez et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…It has been speculated that zinc-dependent MAM binding to LG2 cells results from a direct involvement of zinc in the interactions between MAM and the class II MHC molecule HLA-DR1, since MAM binding to LG2 cells was completely inhibited by the presence of anti-HLA-DR mAb, whereas the anti-HLA-DP, anti-HLA-DQ, anti-CD40, or anti-MHC class I mAbs had no effect (Etongue-Mayer et al, 2002). Alternatively, zinc could be involved in the formation of a MAM homodimer, which may be required for the protein's biological function (Langlois et al, 2003). Indeed, our recent structural study revealed that MAM forms an asymmetric homodimer that can cross-link two MHC molecules (Zhao et al, 2004a).…”

Section: Discussionmentioning

confidence: 99%

“…It was reported that the superantigenic activity of MAM via MHC class II molecules is Zn 2+ dependent, and that Zn 2+ may trigger the dimerization of MAM (Bernatchez et al, 1997;Etongue-Mayer et al, 2002;Langlois et al, 2003). However, in the crystal structure of the dimerized MAM/HLA-DR1/HA complex (Zhao et al, 2004a), we could not detect Zn 2+ ion at either the interface of the MAM/HLA-DR1 complex or at the interface of the MAM homodimer, even though the crystallization buffer contained 1 mM Zn(OAc) 2 (Zhao et al, 2004a,b).…”

Section: Detection Of the Mam Homodimer By Chemical Cross-linkingmentioning

confidence: 99%

“…In addition, there is discrepancy regarding whether Zn 2+ is involved in MAM dimerization (Langlois et al, 2003;Zhao et al, 2004a). It has been proposed that dimerization or oligomerization of the MHC antigens by SAgs is critical for both T-cell activation and T-cell-independent cytokine expression on various human antigen-presenting cells (APCs) (Mehindate et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Mutagenesis, biochemical, and biophysical characterization of Mycoplasma arthritidis-derived mitogen

Li¹,

Zhao²,

Guo³

et al. 2007

Molecular Immunology

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Mycoplasma arthritidis -derived mitogen (MAM) is a superantigen (SAg) that can activate large fractions of T cells bearing particular TCR Vβ elements. Here we report the mutagenesis, biochemical and biophysical studies on the dimerization of MAM in solution. Our studies showed that although MAM mainly exists as a monomer in solution, a small percentage of MAM molecules form homodimer at high protein concentration, regardless of the presence of Zn 2+ . A distinct peak corresponding to a MAM homodimer was detected in the presence of EDTA, using both chemical cross-linking and analytical ultracentrifugation methods. Further mutagenesis studies revealed that single mutation of residues at the interface of the crystallographic dimer of MAM does not significantly affect the dimerization of MAM in solution. Circular dichroism (CD) analysis indicated that addition of Zn 2+ does not induce conformational changes of MAM from its apo-state. Thermal denaturation experiments indicated that addition of Zn 2+ to MAM solution resulted in a decrease of melting point (T m ), whereas addition of EDTA did not affect the T m of MAM. These results imply that there is no defined Zn 2+ -binding site on MAM.

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