Myelin Oligodendrocyte Glycoprotein

Deveren Manley II '19 and Sarah Dendy '19

Contents:

I. Introduction

Myelin oligodendrocyte glycoprotein, or MOG, is a protein found in mammalian neural cells. The model here was generated from observations of mouse protein. It is more than 90% conserved among animals, suggesting physiological importance, but its exact function is unknown. Several aspects of its structure suggest that is plays a role in surface interactions between central nervous system cells. It is localized to cell membranes, it develops in the late stages of myelinogenesis and has the potential to dimerize with itself, all of which support a role as an adhesive.

Hor et al. identified MOG as a potential agent in inherited narcolepsy in humans. A missense mutation changing serine 133 to a cysteine is highly correlated with a narcoleptic phenotype. This mutation alters the subcellular localization of MOG, from exclusively associated with membranes to membrane-bound with clusters in cytoplasm. The altered behavior of the protein may be causative for the disease phenotype.

MOG also interacts extracellularly with the rubella virus. Rubella is an infectious agent causing birth defects or fetal death in developing humans. MOG contacts the glycoprotein envelope of the virus, and introducing MOG to cells which were previously not susceptible to rubella allows them to uptake the virus. Blocking MOG is therefore potentially therapeutic for rubella virus infection.

MOG is best known from studies of multiple sclerosis. MOG is the major protein attacked in the multiple sclerosis autoimmune response. It induces encephalitis when introduced into a susceptible mouse model. These animals suffer neural inflammation and multiple sclerosis-like demyelination, termed experimental allergic encephalomyelitis (EAE). Human multiple sclerosis patients share the elevated levels of MOG autoantibodies, with accompanying symptoms.

II. Structure

Beta-sheets and Alpha Helices

The overall structure of the myelin oligodendrocyte glycoprotein is a .This refers to two β sheets which are relatively planar and are stacked, one above the other. In MOG, one β sheet is an and the other is a . The antiparallel sheet consists of the strands designated A, B, E, and D . The other β sheet is composed of strands A’, G, F, C, C’, and C’’. MOG also has .Series of amino acids characterizes .

Loops

The residues between strands B and C, C’ and C”, and F and G are termed respectively. Collectively, they form a relatively flat face on the molecule. They are relevant to the disease function of the protein because they have been implicated in binding of immune elements to MOG.

Salt Bridge, Core Disulfide Bond

MOG is an Ig-V domain protein, with several structural features characteristic of the family. These include a central disulfide bond packing against a consensus residue, and a central, buried salt bridge.

Arginine-68 forms the with aspartate-92. These residues fall between strands C” and D and strands E and F. The of MOG is formed between cysteine-24 and cysteine-98. These residues fall on strands B and F, which are on opposite β sheets. These bond are both integral to the structure of the molecule, and the spatial orientation of one sheet relative to the other. The mutation described by Hor et al. (2011), associated with narcolepsy, involves alteration of a serine base to a cysteine base, which may form an incorrect central disulfide bond during protein folding. This would severely alter the conformation of the mature protein.

III. Homologies

Comparisons by Clements et al. (2003) showed myelin oligodendrocyte glycoprotein is most structurally similar to sialoadhesin. Sialoadhesin is an adhesive molecule which regulates cell to cell interactions between other cell types. It is particularly common on the surface of macrophages. MOG and sialoadhesin show low sequence homology (24%), but physically resemble each other, in part due to the action of a few conserved regions. These include the cysteines forming the central disulfide bond, as well as arginine and aspartate involved in salt bridge formation.

Mouse MOG has described homologs in humans, rats, cattle, and quokka. Humans have several encephalitogenic proteins which share structural homology, including adenovirus receptor D1 domain (CAR), myelin protein zero (P0), b7-2, and junctional adhesion molecule (JAM). These peptides do not have strong sequence homology with MOG, but share certain conserved residues, specifically in Loops 1, 2, and 3, the region between A and A’, and the C-C’ loop. Conservation of these structural regions creates the characteristic disulfide bonds, salt bridge, and double β sheets which determine three dimensional structure and create physical homologies.

IV. Antibody Binding

In multiple sclerosis, an autoimmune response against MOG triggers demyelination of nerve cells. of MOG complex with antibody to produce this immune response. These are the N-terminal tail and loops 1, 2 and 3. 65% of binding is from loop 3, the F-G loop. This region gains its exact conformation through its association with neighboring amino acids in the correctly-folded structure. When isolated, it is highly strained, and tends to linearize rather than developing the three-dimensional epitope shape. Thus, isolating this region of MOG for immune assays does not typically elicit an immune response, despite its predominance in antibody binding. This has the potential to confound experimental immune response assays.

Interestingly, the encephalitogenic proteins CAR, P0, b7-2, and JAM do not share peptide sequence with MOG in loop 3. They share structural homology, and the similarity of the immune response against them would suggest that they trigger inflammation through a similar pathway to MOG. However, discrepancies in sequence suggest that either these proteins lead to inflammation through another pathway, or that the binding of antibody at these sites is not sequence-specific.

IV. Monomeric vs. Dimeric form

As a crystal, MOG forms a lattice suggestive of a homodimeric form. The extent to which a homodimeric form occurs in vivo remains undetermined. However, the high favorability of these contacts suggest that they may be biologically relevant. Further evidence is the fact that the is extensive, representing 1,800 square angstroms.

The dimer is antiparallel, forming a head-to-tail structure. It forms between three regions of each subunit protein, namely the interconnecting loop between A and A’ strands, the C–C’ loop, and the F–G strand β-hairpin. These regions represent one of the two β sheets, and elements that are between the β sheets. In a dimerized form, there are ten direct hydrogen bonds between the molecules.

The dimerized form may be relevant to observed encephalitic effects from exogenous MOG introduction. If MOG dimerizes during growth, the result is the burying of several significant residues. These include amino acids 101-106, which form part of the F-G loop essential to antibody recognition of the protein. Thus, immune response in this system is primarily against the monomeric form of the protein. Epitope residues are hidden when MOG is in a homodimer. region of overlap is identified in purple and regions contacted by antibody or complementary protein monomer are identified by red and green respectively.

V. Phenylalanine 44-Implications for in-vivo Behavior

Sialoadhesin is the strongest structural analog to MOG. The sialoadhesin protein interacts with its ligand, sialic acid, through tyrosine-44. This residue has its analog in MOG in the amino acid . This residue is a good target for investigating possible ligands of MOG. One suggestion is complement component 1q (C1q), which is an element of the immune system and has been shown to interact with MOG in vitro. The relatively exposed position of phenylalanine-44, between the C and C’ strands, supports this possibility.


VI. References

Clements Craig S., Reid Hugh H., Beddoe Travis, Tynan Fleur E., Perugini Matthew A., Johns Terrance G., Bernard Claude C. A, & Rossjohn Jamie (2003) The crystal structure of myelin oligodendrocyte glycoprotein, a key autoantigen in multiple sclerosis. PNAS 100, 19:11059–11064 http://www.pnas.org/content/pnas/100/19/11059.full.pdf

Cong Haolong, Jiang Yue, & Tien Po (2011) Identification of the myelin oligodendrocyte glycoprotein as a cellular receptor for rubella virus. J. Virol doi:10.1128/JVI.05398-11 http://jvi.asm.org/content/early/2011/08/31/JVI.05398-11.full.pdf

Dey Sucharita, Pal Arumay, Chakrabarti Pinak, & Janin Joël (2010) The subunit interfaces of weakly associated homodimeric proteins. Jour. Mol. Bio. 398, 1: 146-160 https://www.sciencedirect.com/science/article/pii/S0022283610001786

Hor Hyun, Bartesaghi Luca, Kutalik Zoltán,Vicário José L., Andrés Clarade, Pfister Corinne, Lammers Gert J., Guex Nicolas, Chrast Roman, Tafti Mehdi, & Peraita-Adrados Rosa (2011) A missense mutation in myelin oligodendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy. AJHG 89, 3: 474-479 https://www.sciencedirect.com/science/article/pii/S0002929711003570

Mathey Emily, Breithaupt Constanze, Schubart Anna S., & Linington Christopher (2004) Sorting the wheat from the chaff: identifying demyelinating components of the myelin oligodendrocyte glycoprotein (MOG)-specific autoantibody repertoire Eur. J. Immunol. 34: 2065–2071 https://onlinelibrary.wiley.com/doi/pdf/10.1002/eji.200425291

Menge Til, von Bdingen Hans-Christian, Lalive Patrice H & Genain Claude P (2007) Relevant antibody subsets against MOG recognize conformational epitopes exclusively exposed in solid-phase ELISA. Eur. J. Immunol. 37: 3229–3239 https://onlinelibrary.wiley.com/doi/pdf/10.1002/eji.200737249

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