Article

Disruption of perlecan binding and matrix assembly by post-translational or genetic disruption of dystroglycan function

Department of Physiology and Biophysics, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, 400 Eckstein Medical Building, Iowa City, IA 52242, USA.
FEBS Letters (Impact Factor: 3.34). 09/2005; 579(21):4792-6. DOI: 10.1016/j.febslet.2005.07.059
Source: PubMed

ABSTRACT Dystroglycan is a cell-surface matrix receptor that requires LARGE-dependent glycosylation for laminin binding. Although the interaction of dystroglycan with laminin has been well characterized, less is known about the role of dystroglycan glycosylation in the binding and assembly of perlecan. We report reduced perlecan-binding activity and mislocalization of perlecan in the LARGE-deficient Large(myd) mouse. Cell-surface ligand clustering assays show that laminin polymerization promotes perlecan assembly. Solid-phase binding assays provide evidence for the first time of a trimolecular complex formation of dystroglycan, laminin and perlecan. These data suggest functional disruption of the trimolecular complex in glycosylation-deficient muscular dystrophy.

0 Followers
 · 
104 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in fukutin related protein (FKRP) underlie a group of muscular dystrophies associated with the hypoglycosylation of α-dystroglycan (α-DG), a proportion of which show central nervous system involvement. Our original FKRP knock down mouse (FKRP(KD)) replicated many of the characteristics seen in patients at the severe end of the dystroglycanopathy spectrum but died perinatally precluding its full phenotyping and use in testing potential therapies. We have now overcome this by crossing FKRP(KD) mice with those expressing Cre recombinase under the Sox1 promoter. Due to our original targeting strategy this has resulted in the restoration of Fkrp levels in the central nervous system but not the muscle, thereby generating a new model (FKRPMD) which develops a progressive muscular dystrophy resembling what is observed in limb girdle muscular dystrophy. Like-acetylglucosaminyltransferase (LARGE) is a bifunctional glycosyltransferase previously shown to hyperglycosylate α-dystroglycan. In order to investigate the therapeutic potential of LARGE up-regulation we have now crossed the FKRPMD line with one overexpressing LARGE and show that, contrary to expectation, this results in a worsening of the muscle pathology implying that any future strategies based upon LARGE up-regulation require careful management.
    Human Molecular Genetics 11/2013; 23(7). DOI:10.1093/hmg/ddt577 · 6.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dystroglycan is a highly glycosylated peripheral membrane protein that functions as a cell surface receptor for proteins in the extracellular matrices and synapses. O-Mannosyl glycosylation is necessary for the ligand-binding activities of dystroglycan and a unique "post-phosphoryl moiety" modified via a phosphodiester linkage on the O-mannose likely forms the ligand-binding domain. Several proteins are involved in the process of this modification, the mechanism for which appears highly ordered. In various tissues, dystroglycan plays important physiological roles such as maintenance of muscle cell viability and structural development of the brain. Conversely, abnormal glycosylation causes a group of muscular dystrophy, collectively called "dystroglycanopathy," which is often associated with brain abnormalities including type II lissencephaly and mental retardation. Here, we will be reviewing the structure, modification pathway, and physiological roles of dystroglycan glycosylation as well as their involvement in human diseases.
    Trends in Glycoscience and Glycotechnology 01/2014; 26(149):41-57. DOI:10.4052/tigg.26.41 · 0.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: GOLPH3 is a highly conserved protein found across the eukaryotic lineage. The yeast homologue, Vps74p, interacts with and maintains the Golgi localization of several mannosyltransferases, which is subsequently critical for N- and O- glycosylation in yeast. Here, T7 phage display was used to screen for novel interacting partners of GOLPH3. GOLPH3 was found to bind to POMGnT1 which is involved in O-mannosylation of α-dystroglycan. We found that loss of this interaction resulted in the inability of POMGnT1 to localize to the Golgi and reduced the functional glycosylation of α-dystroglycan. In addition, we showed that three clinically relevant mutations in POMGnT1 mislocalized to the ER highlighting the importance of identifying the molecular mechanisms responsible for Golgi localization of glycosyltransferases. Our findings reveal a novel role for GOLPH3 in mediating the Golgi localization of POMGnT1.
    Journal of Biological Chemistry 04/2014; 289(21). DOI:10.1074/jbc.M114.548305 · 4.60 Impact Factor

Full-text (2 Sources)

Download
34 Downloads
Available from
May 28, 2014