PDBsum entry 5n4h

Cell adhesion

PDB id: 5n4h

Contents

Protein chain

231 a.a.

Ligands

EDO ×2

PEG

Waters ×196

PDB id:

5n4h

Name:

Cell adhesion

Title:

Crystal structure of the d109n mutant of the mouse alpha-dystroglycan n-terminal region

Structure:

Dystroglycan. Chain: a. Synonym: dystrophin-associated glycoprotein 1. Engineered: yes. Mutation: yes. Other_details: dg hypoglycosylated mutant

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Tissue: skeletal muscle. Gene: dag1, dag-1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008

Resolution:

1.70Å R-factor: 0.160 R-free: 0.182

Authors:

A.Cassetta,S.Covaceuszach,A.Brancaccio,F.Sciandra,M.Bozzi, M.G.Bigotti,P.V.Konarev

Key ref:

S.Covaceuszach et al. (2017). The effect of the pathological V72I, D109N and T190M missense mutations on the molecular structure of α-dystroglycan. PLoS One, 12, e0186110. PubMed id: 29036200

Date:

10-Feb-17 Release date: 01-Nov-17

Protein chain

Q62165  (DAG1_MOUSE) -  Dystroglycan 1 from Mus musculus

Seq: 893 a.a.

Struc: 231 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

PLoS One 12:e0186110 (2017)

PubMed id: 29036200

The effect of the pathological V72I, D109N and T190M missense mutations on the molecular structure of α-dystroglycan.

S.Covaceuszach, M.Bozzi, M.G.Bigotti, F.Sciandra, P.V.Konarev, A.Brancaccio, A.Cassetta.

ABSTRACT

Dystroglycan (DG) is a highly glycosylated protein complex that links the cytoskeleton with the extracellular matrix, mediating fundamental physiological functions such as mechanical stability of tissues, matrix organization and cell polarity. A crucial role in the glycosylation of the DG α subunit is played by its own N-terminal region that is required by the glycosyltransferase LARGE. Alteration in this O-glycosylation deeply impairs the high affinity binding to other extracellular matrix proteins such as laminins. Recently, three missense mutations in the gene encoding DG, mapped in the α-DG N-terminal region, were found to be responsible for hypoglycosylated states, causing congenital diseases of different severity referred as primary dystroglycanopaties.To gain insight on the molecular basis of these disorders, we investigated the crystallographic and solution structures of these pathological point mutants, namely V72I, D109N and T190M. Small Angle X-ray Scattering analysis reveals that these mutations affect the structures in solution, altering the distribution between compact and more elongated conformations. These results, supported by biochemical and biophysical assays, point to an altered structural flexibility of the mutant α-DG N-terminal region that may have repercussions on its interaction with LARGE and/or other DG-modifying enzymes, eventually reducing their catalytic efficiency.