title: Molecular recognition by LARGE is essential for expression of functional dystroglycan.
abstract: Reduced ligand binding activity of alpha-dystroglycan is associated with muscle and central nervous system pathogenesis in a growing number of muscular dystrophies. Posttranslational processing of alpha-dystroglycan is generally accepted to be critical for the expression of functional dystroglycan. Here we show that both the N-terminal domain and a portion of the mucin-like domain of alpha-dystroglycan are essential for high-affinity laminin-receptor function. Posttranslational modification of alpha-dystroglycan by glycosyltransferase, LARGE, occurs within the mucin-like domain, but the N-terminal domain interacts with LARGE, defining an intracellular enzyme-substrate recognition motif necessary to initiate functional glycosylation. Gene replacement in dystroglycan-deficient muscle demonstrates that the dystroglycan C-terminal domain is sufficient only for dystrophin-glycoprotein complex assembly, but to prevent muscle degeneration the expression of a functional dystroglycan through LARGE recognition and glycosylation is required. Therefore, molecular recognition of dystroglycan by LARGE is a key determinant in the biosynthetic pathway to produce mature and functional dystroglycan.
authors.affiliation: Howard Hughes Medical Institute, Department of Physiology and Biophysics, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Motoi
authors.initials: M
authors.lastname: Kanagawa
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Saito
authors.forename: Stefan
authors.initials: S
authors.lastname: Kunz
authors.forename: Takako
authors.initials: T
authors.lastname: Yoshida-Moriguchi
authors.forename: Rita
authors.initials: R
authors.lastname: Barresi
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: Kobayashi
authors.forename: John
authors.initials: J
authors.lastname: Muschler
authors.forename: Jan P
authors.initials: JP
authors.lastname: Dumanski
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Michele
authors.forename: Michael B A
authors.initials: MB
authors.lastname: Oldstone
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D049030:Dystroglycans; D006031:Glycosylation; D016695:Glycosyltransferases / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011817:Rabbits; D017474:Receptors, Laminin / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology
chemical_list: D003598:Cytoskeletal Proteins; D008562:Membrane Glycoproteins; D017474:Receptors, Laminin; D011993:Recombinant Fusion Proteins; D049030:Dystroglycans; D016695:Glycosyltransferases