5llk | pdb_00005llk
Crystal structure of human alpha-dystroglycan
Structural highlights
Disease[DAG1_HUMAN] Defects in DAG1 are the cause of muscular dystrophy-dystroglycanopathy limb-girdle type C7 (MDDGC7) [MIM:613818]. An autosomal recessive muscular dystrophy showing onset in early childhood, and associated with mental retardation without structural brain anomalies. Note=MDDGC7 is caused by DAG1 mutations that interfere with normal post-translational processing, resulting in defective DAG1 glycosylation and impaired interactions with extracellular-matrix components. Other muscular dystrophy-dystroglycanopathies are caused by defects in enzymes involved in protein O-glycosylation.[1] Function[DAG1_HUMAN] The dystroglycan complex is involved in a number of processes including laminin and basement membrane assembly, sarcolemmal stability, cell survival, peripheral nerve myelination, nodal structure, cell migration, and epithelial polarization.[2] [3] [4] [5] Alpha-dystroglycan is an extracellular peripheral glycoprotein that acts as a receptor for both extracellular matrix proteins containing laminin-G domains, and for certain adenoviruses. Receptor for laminin-2 (LAMA2) and agrin in peripheral nerve Schwann cells. Also acts as a receptor for M.leprae in peripheral nerve Schwann cells but only in the presence of the G-domain of LAMA2, and for lymphocytic choriomeningitis virus, Old World Lassa fever virus, and clade C New World arenaviruses.[6] [7] [8] [9] Beta-dystroglycan is a transmembrane protein that plays important roles in connecting the extracellular matrix to the cytoskeleton. Acts as a cell adhesion receptor in both muscle and non-muscle tissues. Receptor for both DMD and UTRN and, through these interactions, scaffolds axin to the cytoskeleton. Also functions in cell adhesion-mediated signaling and implicated in cell polarity.[10] [11] [12] [13] Publication Abstract from PubMedDystroglycan (DG), composed of alpha and beta subunits, belongs to the dystrophin-associated glycoprotein complex. alpha-DG is an extracellular matrix protein that undergoes a complex post-translational glycosylation process. The bifunctional glycosyltransferase like-acetylglucosaminyltransferase (LARGE) plays a crucial role in the maturation of alpha-DG, enabling its binding to laminin. We have already structurally analyzed the N-terminal region of murine alpha-DG (alpha-DG-Nt) and of a pathological single point mutant that may affect recognition of LARGE, although the structural features of the potential interaction between LARGE and DG remain elusive. We now report on the crystal structure of the wild-type human alpha-DG-Nt that has allowed us to assess the reliability of our murine crystallographic structure as a alpha-DG-Nt general model. Moreover, we address for the first time both structures in solution. Interestingly, small-angle X-ray scattering (SAXS) reveals the existence of two main protein conformations ensembles. The predominant species is reminiscent of the crystal structure, while the less populated one assumes a more extended fold. A comparative analysis of the human and murine alpha-DG-Nt solution structures reveals that the two proteins share a common interdomain flexibility and population distribution of the two conformers. This is confirmed by the very similar stability displayed by the two orthologs as assessed by biochemical and biophysical experiments. These results highlight the need to take into account the molecular plasticity of alpha-DG-Nt in solution, as it can play an important role in the functional interactions with other binding partners. Structural flexibility of human alpha-dystroglycan.,Covaceuszach S, Bozzi M, Bigotti MG, Sciandra F, Konarev PV, Brancaccio A, Cassetta A FEBS Open Bio. 2017 Jul 17;7(8):1064-1077. doi: 10.1002/2211-5463.12259., eCollection 2017 Aug. PMID:28781947[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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