Mammalian O-mannosylation: unsolved questions of structure/function.

Post-translational modification of polypeptides with glycans increases the diversity of the structures of proteins and imparts increased functional diversity. Here, we review the current literature on a relatively new O-glycosylation pathway, the mammalian O-mannosylation pathway. The importance of O-mannosylation is illustrated by the fact that O-mannose glycan structures play roles in a variety of processes including viral entry into cells, metastasis, cell adhesion, and neuronal development. Furthermore, mutations in the enzymes of this pathway are causal for a variety of congenital muscular dystrophies. Here we highlight the protein substrates, glycan structures, and enzymes involved in O-mannosylation as well as our gaps in understanding structure/function relationships in this biosynthetic pathway.

[1]  K. Hoyte,et al.  Overexpression of the cytotoxic T cell GalNAc transferase in skeletal muscle inhibits muscular dystrophy in mdx mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[2]  R. U. Margolis,et al.  Demonstration of mammalian protein O-mannosyltransferase activity: coexpression of POMT1 and POMT2 required for enzymatic activity. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[3]  K. Campbell,et al.  Glycomic Analyses of Mouse Models of Congenital Muscular Dystrophy* , 2011, The Journal of Biological Chemistry.

[4]  P. M. Nienaber,et al.  Fukutin-related Protein Associates with the Sarcolemmal Dystrophin-Glycoprotein Complex* , 2007, Journal of Biological Chemistry.

[5]  Nicolle H. Packer,et al.  Mucin‐type O‐glycosylation – putting the pieces together , 2010, The FEBS journal.

[6]  S. Carbonetto,et al.  Dystroglycan-α, a dystrophin-associated glycoprotein, is a functional agrin receptor , 1994, Cell.

[7]  P. Stanley,et al.  Mouse Large Can Modify Complex N- and Mucin O-Glycans on α-Dystroglycan to Induce Laminin Binding* , 2005, Journal of Biological Chemistry.

[8]  C. Walsh,et al.  Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. , 2002, American journal of human genetics.

[9]  I. Kanazawa,et al.  Structures of Sialylated O-Linked Oligosaccharides of Bovine Peripheral Nerve α-Dystroglycan , 1997, The Journal of Biological Chemistry.

[10]  Paul T Martin,et al.  Genetic defects in muscular dystrophy. , 2010, Methods in enzymology.

[11]  Susan C. Brown,et al.  Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. , 2001, Human molecular genetics.

[12]  N. Smalheiser,et al.  Structural Analysis of Sequences O-Linked to Mannose Reveals a Novel Lewis X Structure in Cranin (Dystroglycan) Purified from Sheep Brain* , 1998, The Journal of Biological Chemistry.

[13]  Kenji Nakamura,et al.  Targeted disruption of exon 52 in the mouse dystrophin gene induced muscle degeneration similar to that observed in Duchenne muscular dystrophy. , 1997, Biochemical and biophysical research communications.

[14]  Gerhard K. H. Przemeck,et al.  Targeted disruption of the Walker-Warburg syndrome gene Pomt1 in mouse results in embryonic lethality. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Susan C. Brown,et al.  Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. , 2003, Human molecular genetics.

[16]  Doron Betel,et al.  Cloning and expression of a novel UDP-GlcNAc:alpha-D-mannoside beta1,2-N-acetylglucosaminyltransferase homologous to UDP-GlcNAc:alpha-3-D-mannoside beta1,2-N-acetylglucosaminyltransferase I. , 2002, The Biochemical journal.

[17]  Martin Brockington,et al.  Localization and functional analysis of the LARGE family of glycosyltransferases: significance for muscular dystrophy. , 2005, Human molecular genetics.

[18]  T. Südhof,et al.  A stoichiometric complex of neurexins and dystroglycan in brain , 2001, The Journal of cell biology.

[19]  J. Hewitt,et al.  Mutant glycosyltransferase and altered glycosylation of alpha-dystroglycan in the myodystrophy mouse. , 2001, Nature genetics.

[20]  S. Carbonetto,et al.  Dystroglycan-alpha, a dystrophin-associated glycoprotein, is a functional agrin receptor. , 1994, Cell.

[21]  R. U. Margolis,et al.  Brain Contains HNK-1 Immunoreactive O-Glycans of the Sulfoglucuronyl Lactosamine Series that Terminate in 2-Linked or 2,6-Linked Hexose (Mannose)* , 1997, The Journal of Biological Chemistry.

[22]  R. U. Margolis,et al.  Novel mannitol-containing oligosaccharides obtained by mild alkaline borohydride treatment of a chondroitin sulfate proteoglycan from brain. , 1979, The Journal of biological chemistry.

[23]  Takashi Fujikado,et al.  Pikachurin, a dystroglycan ligand, is essential for photoreceptor ribbon synapse formation , 2008, Nature Neuroscience.

[24]  K. Campbell,et al.  LARGE can functionally bypass α-dystroglycan glycosylation defects in distinct congenital muscular dystrophies , 2004, Nature Medicine.

[25]  S. Fujii,et al.  N-Acetylglucosaminyltransferase IX Acts on the GlcNAcβ1,2-Manα1-Ser/Thr Moiety, Forming a 2,6-Branched Structure in Brain O-Mannosyl Glycan* , 2004, Journal of Biological Chemistry.

[26]  N. Nakanishi,et al.  LARGE2 facilitates the maturation of alpha-dystroglycan more effectively than LARGE. , 2005, Biochemical and biophysical research communications.

[27]  J. Dennis,et al.  Adaptive Regulation at the Cell Surface by N‐Glycosylation , 2009, Traffic.

[28]  R. U. Margolis,et al.  High prevalence of 2-mono- and 2,6-di-substituted manol-terminating sequences among O-glycans released from brain glycopeptides by reductive alkaline hydrolysis. , 1999, European journal of biochemistry.

[29]  K. Campbell,et al.  Muscular dystrophies involving the dystrophin-glycoprotein complex: an overview of current mouse models. , 2002, Current opinion in genetics & development.

[30]  J. Lowe,et al.  Role of glycosylation in development. , 2003, Annual review of biochemistry.

[31]  J. Hewitt,et al.  Glycosylation defects: a new mechanism for muscular dystrophy? , 2003, Human molecular genetics.

[32]  N. Smalheiser,et al.  The relationship between perlecan and dystroglycan and its implication in the formation of the neuromuscular junction. , 1998, Cell adhesion and communication.

[33]  Liping Yu,et al.  O-Mannosyl Phosphorylation of Alpha-Dystroglycan Is Required for Laminin Binding , 2010, Science.

[34]  J. Ervasti,et al.  Site Mapping and Characterization of O-Glycan Structures on α-Dystroglycan Isolated from Rabbit Skeletal Muscle* , 2010, The Journal of Biological Chemistry.

[35]  I. Kanazawa,et al.  An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy , 1998, Nature.

[36]  K. Campbell,et al.  Dystroglycan: from biosynthesis to pathogenesis of human disease , 2006, Journal of Cell Science.

[37]  K. Campbell,et al.  Identification of alpha-dystroglycan as a receptor for lymphocytic choriomeningitis virus and Lassa fever virus. , 1998, Science.

[38]  M. Mizuno,et al.  Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. , 2001, Developmental cell.

[39]  F. Muntoni,et al.  Muscular dystrophies due to glycosylation defects , 2008, Neurotherapeutics.

[40]  O. Ibraghimov-Beskrovnaya,et al.  Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix , 1992, Nature.

[41]  K. Davies,et al.  Muscular Dystrophy—Reason for Optimism? , 2002, Cell.

[42]  Susan C. Brown,et al.  Defective glycosylation in congenital muscular dystrophies , 2004, Current opinion in neurology.

[43]  Eric P. Hoffman,et al.  Dystrophin: The protein product of the duchenne muscular dystrophy locus , 1987, Cell.

[44]  Susan C. Brown,et al.  Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. , 2001, American journal of human genetics.

[45]  K. Campbell,et al.  Posttranslational Modification of α-Dystroglycan, the Cellular Receptor for Arenaviruses, by the Glycosyltransferase LARGE Is Critical for Virus Binding , 2005, Journal of Virology.

[46]  Munhyang Lee,et al.  Worldwide distribution and broader clinical spectrum of muscle-eye-brain disease. , 2003, Human molecular genetics.

[47]  Takehiro Suzuki,et al.  Regulation of Mammalian Protein O-Mannosylation , 2007, Journal of Biological Chemistry.

[48]  I. Dunham,et al.  The human LARGE gene from 22q12.3-q13.1 is a new, distinct member of the glycosyltransferase gene family. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Leszek Rychlewski,et al.  Comprehensive classification of nucleotidyltransferase fold proteins: identification of novel families and their representatives in human , 2009, Nucleic acids research.

[50]  I. Kanazawa,et al.  Structures of sialylated O-linked oligosaccharides of bovine peripheral nerve alpha-dystroglycan. The role of a novel O-mannosyl-type oligosaccharide in the binding of alpha-dystroglycan with laminin. , 1997, The Journal of biological chemistry.

[51]  F. Muntoni,et al.  Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker–Warburg syndrome , 2004, Journal of Medical Genetics.

[52]  T. Willer,et al.  Characterization of POMT2, a novel member of the PMT protein O-mannosyltransferase family specifically localized to the acrosome of mammalian spermatids. , 2002, Glycobiology.

[53]  Jonas Nilsson,et al.  Characterization of site-specific O-glycan structures within the mucin-like domain of alpha-dystroglycan from human skeletal muscle. , 2010, Glycobiology.

[54]  T. Endo O-mannosyl glycans in mammals. , 1999, Biochimica et biophysica acta.

[55]  P. Stanley,et al.  Mutational and functional analysis of Large in a novel CHO glycosylation mutant. , 2009, Glycobiology.

[56]  A. Coloma,et al.  Identification of a human homolog of the Drosophila rotated abdomen gene (POMT1) encoding a putative protein O-mannosyl-transferase, and assignment to human chromosome 9q34.1. , 1999, Genomics.

[57]  N. Nakanishi,et al.  LARGE2 facilitates the maturation of α-dystroglycan more effectively than LARGE , 2005 .

[58]  J. Ervasti,et al.  Membrane organization of the dystrophin-glycoprotein complex , 1991, Cell.

[59]  Michael D. Henry,et al.  Loss of α-Dystroglycan Laminin Binding in Epithelium-derived Cancers Is Caused by Silencing of LARGE*S⃞♦ , 2009, Journal of Biological Chemistry.

[60]  K. Matsumura,et al.  Detection of O-mannosyl glycans in rabbit skeletal muscle α-dystroglycan , 1998 .

[61]  P. Stanley,et al.  Mouse large can modify complex N- and mucin O-glycans on alpha-dystroglycan to induce laminin binding. , 2005, The Journal of biological chemistry.

[62]  J. Hewitt,et al.  Mutant glycosyltransferase and altered glycosylation of α-dystroglycan in the myodystrophy mouse , 2001, Nature Genetics.

[63]  S. Fujii,et al.  N-Acetylglucosaminyltransferase IX acts on the GlcNAc beta 1,2-Man alpha 1-Ser/Thr moiety, forming a 2,6-branched structure in brain O-mannosyl glycan. , 2004, The Journal of biological chemistry.

[64]  L. Kunkel,et al.  Diagnosis and cell-based therapy for Duchenne muscular dystrophy in humans, mice, and zebrafish , 2006, Journal of Human Genetics.

[65]  Doron Betel,et al.  Cloning and expression of a novel UDP-GlcNAc:α-d-mannoside β1,2-N-acetylglucosaminyltransferase homologous to UDP-GlcNAc:α-3-d-mannoside β1,2-N-acetylglucosaminyltransferase I , 2002 .

[66]  Paul T Martin,et al.  Congenital muscular dystrophies involving the O-mannose pathway. , 2007, Current molecular medicine.

[67]  Shun–ichi Kobayashi Tokyo campus rising , 1998, Nature.