4WIQ

The structure of Murine alpha-Dystroglycan T190M mutant N-terminal domain.

Summary for 4WIQ

• Entry DOI: 10.2210/pdb4wiq/pdb
• Related: 1U2C
• Descriptor: Dystroglycan, 1,2-ETHANEDIOL, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: mutant, dystroglycanopathy, structural protein
• Biological source: Mus musculus (Mouse)
• Cellular location: Alpha-dystroglycan: Secreted, extracellular space . Beta-dystroglycan: Cell membrane ; Single-pass type I membrane protein : Q62165
• Total number of polymer chains: 1
• Total formula weight: 28669.06

Authors

Brancaccio, A.,Lamba, D.,Cassetta, A.,Bozzi, M.,Covaceuszach, S.,Sciandra, F.,Bigotti, M.G. (deposition date: 2014-09-26, release date: 2015-05-13, Last modification date: 2024-10-23)

Primary citation

Bozzi, M.,Cassetta, A.,Covaceuszach, S.,Bigotti, M.G.,Bannister, S.,Hubner, W.,Sciandra, F.,Lamba, D.,Brancaccio, A.
The Structure of the T190M Mutant of Murine alpha-Dystroglycan at High Resolution: Insight into the Molecular Basis of a Primary Dystroglycanopathy.
Plos One, 10:e0124277-e0124277, 2015

PubMed Abstract: The severe dystroglycanopathy known as a form of limb-girdle muscular dystrophy (LGMD2P) is an autosomal recessive disease caused by the point mutation T192M in α-dystroglycan. Functional expression analysis in vitro and in vivo indicated that the mutation was responsible for a decrease in posttranslational glycosylation of dystroglycan, eventually interfering with its extracellular-matrix receptor function and laminin binding in skeletal muscle and brain. The X-ray crystal structure of the missense variant T190M of the murine N-terminal domain of α-dystroglycan (50-313) has been determined, and showed an overall topology (Ig-like domain followed by a basket-shaped domain reminiscent of the small subunit ribosomal protein S6) very similar to that of the wild-type structure. The crystallographic analysis revealed a change of the conformation assumed by the highly flexible loop encompassing residues 159-180. Moreover, a solvent shell reorganization around Met190 affects the interaction between the B1-B5 anti-parallel strands forming part of the floor of the basket-shaped domain, with likely repercussions on the folding stability of the protein domain(s) and on the overall molecular flexibility. Chemical denaturation and limited proteolysis experiments point to a decreased stability of the T190M variant with respect to its wild-type counterpart. This mutation may render the entire L-shaped protein architecture less flexible. The overall reduced flexibility and stability may affect the functional properties of α-dystroglycan via negatively influencing its binding behavior to factors needed for dystroglycan maturation, and may lay the molecular basis of the T190M-driven primary dystroglycanopathy.

PubMed: 25932631
DOI: 10.1371/journal.pone.0124277

Experimental method

X-RAY DIFFRACTION (1.59 Å)