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

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Abstract

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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Abbreviations

ADP:

Adenosine diphosphate

BAEE:

α-N-benzoyl-l-arginine ethyl ester

C1–C8:

MBP charge components 1–8 (h—human, b—bovine, rm—recombinant murine)

CaM:

Calmodulin

Cit:

Citrulline

Cit-MBP:

Citrullinated (deiminated) MBP

CNS:

Central nervous system

DAG:

Diacylglycerol

EAE:

Experimental allergic/autoimmune encephalomyelitis

EPR:

Electron paramagnetic resonance

GFAP:

Glial fibrillary acidic protein

Golli:

Genes of the oligodendrocyte lineage

HPLC:

High-performance liquid chromatography

MAP:

Microtubule-associated protein

MARCKS:

Myristoylated alanine-rich C kinase substrate

MBP:

Myelin basic protein (hMBP human, bMBP bovine, mMBP murine, rmMBP recombinant murine)

MOG:

Myelin/oligodendrocyte glycoprotein

MS:

Multiple sclerosis

NADP+/NADPH:

Nicotinamide adenine dinucleotide phosphate (oxidised/reduced)

PAD:

Peptidylarginine deiminase, EC 3.5.3.15

PAGE:

Polyacrylamide gel electrophoresis

PI:

Phosphatidylinositol

PLC:

Phospholipase C

PRMT:

Protein-Arg-N-methyltransferase

rmC1, rmC8:

Recombinant murine analogues of natural C1, C8 isomers

SDS:

Sodium dodecyl sulphate

SDSL:

Site-directed spin labelling

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Acknowledgments

Our work has been supported by grants to GH from the Natural Sciences and Engineering Research Council of Canada, the Multiple Sclerosis Society of Canada (MSSC), and the Canadian Institutes for Health Research. AAM is the recipient of an MSSC Doctoral Studentship. Dr. Lillian DeBruin provided Fig. 4. We are grateful to many colleagues, past and present, but particularly Drs. Noboru Ishiyama, Ian Bates, and Christopher Hill whose work and ideas permeate this review in an unravellable way, and to Drs. Mario Moscarello and Joan Boggs (Hospital for Sick Children, Toronto) with whom we have collaborated rewardingly. Drs. Tony and Celia Campagnoni, University of California at Los Angeles, have always been an inspiration and support to us, for which we are grateful.

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  1. Department of Molecular and Cellular Biology, and Biophysics Interdepartmental Group, University of Guelph, 50 Stone Road East, Guelph, ON, Canada, N1G 2W1

    George Harauz & Abdiwahab A. Musse

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  1. George Harauz
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Correspondence to George Harauz.

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Special issue dedicated to Drs. Anthony and Celia Campagnoni.

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Harauz, G., Musse, A.A. A Tale of Two Citrullines—Structural and Functional Aspects of Myelin Basic Protein Deimination in Health and Disease. Neurochem Res 32, 137–158 (2007). https://doi.org/10.1007/s11064-006-9108-9

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