Molecular recognition by LARGE is essential for expression of functional dystroglycan.
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.
Kanagawa
Motoi
M
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.
Saito
Fumiaki
F
Kunz
Stefan
S
Yoshida-Moriguchi
Takako
T
Barresi
Rita
R
Kobayashi
Yvonne M
YM
Muschler
John
J
Dumanski
Jan P
JP
Michele
Daniel E
DE
Oldstone
Michael B A
MB
Campbell
Kevin P
KP
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
D003598:Cytoskeletal Proteins; D008562:Membrane Glycoproteins; D017474:Receptors, Laminin; D011993:Recombinant Fusion Proteins; D049030:Dystroglycans; D016695:Glycosyltransferases