O -Mannosylation and human disease
- PDF / 384,241 Bytes
- 9 Pages / 595.276 x 790.866 pts Page_size
- 83 Downloads / 140 Views
Cellular and Molecular Life Sciences
REVIEW
O-Mannosylation and human disease Christina M. Dobson • Samuel J. Hempel Stephanie H. Stalnaker • Ryan Stuart • Lance Wells
•
Received: 22 August 2012 / Revised: 2 October 2012 / Accepted: 8 October 2012 Ó Springer Basel 2012
Abstract Glycosylation of proteins is arguably the most prevalent co- and post-translational modification. It is responsible for increased heterogeneity and functional diversity of proteins. Here we discuss the importance of one type of glycosylation, specifically O-mannosylation and its relationship to a number of human diseases. The most widely studied O-mannose modified protein is alphadystroglycan (a-DG). Recent studies have focused intensely on a-DG due to the severity of diseases associated with its improper glycosylation. O-mannosylation of a-DG is involved in cancer metastasis, arenavirus entry, and multiple forms of congenital muscular dystrophy [1, 2]. In this review, we discuss the structural and functional characteristics of O-mannose-initiated glycan structures on a-DG, enzymes involved in the O-mannosylation pathway, and the diseases that are a direct result of disruptions within this pathway.
predominant O-mannosyl glycan structures observed is the O-mannosyl tetrasaccharide (Siaa3Galb4GlcNAcb2ManaSer/Thr), which was first identified on a-DG purified from bovine peripheral nerve tissue [4]. a-DG is an integral glycoprotein of the dystrophin-glycoprotein complex (DGC) that serves to connect the actin cytoskeleton with the extracellular matrix (Fig. 1) by interacting with ECM proteins such as laminin in a glycosylation-dependent manner [5, 6]. Disruptions in the O-mannosylation pathway that lead to hypoglycosylation of a-DG are causative for several forms of congenital muscular dystrophy, and promote metastasis of many cancerous cell lines [7, 8]. In addition to binding to proteins of the ECM, a-DG is a cell surface receptor for several arenaviruses that bind specifically to O-mannosyl structures to facilitate entry into the host cell [9–11].
Keywords Alpha-dystroglycan Arenavirus Cancer LARGE ISPD Metastasis Congenital muscular dystrophy Dystroglycanopathy
Dystroglycan
Introduction O-mannosyl glycans were first reported on mammalian proteins over 30 years ago, when analyzing a proteoglycan-enriched fraction of brain lysate [3]. One of the most
C. M. Dobson S. J. Hempel S. H. Stalnaker R. Stuart L. Wells (&) Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA e-mail: [email protected]
Dystroglycan, or Cranin as it was originally named, was first identified over two decades ago when isolated from embryonic chicken brains [12]. DG is widely expressed among all tissue types but is more prevalent in skeletal muscle and brain. The dystroglycan gene, DAG1, encodes a single polypeptide that is later post-translationally cleaved into two non-covalently bound subunits a- and b- dystroglycan (a-DG and b-DG) [13]. The b–subunit is a transme
Data Loading...
