Journal
JOURNAL OF CHEMICAL INFORMATION AND MODELING
Volume 60, Issue 6, Pages 3145-3156Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.0c00281
Keywords
-
Categories
Funding
- Wellcome Trust Career Reentry Fellowship [097350/Z/11/Z]
- AFM (French Telethon) [20009]
- Wellcome Trust [097350/Z/11/Z] Funding Source: Wellcome Trust
Ask authors/readers for more resources
The acetylglucosaminyltransferase-like protein LARGE1 is an enzyme that is responsible for the final steps of the post-translational modifications of dystroglycan (DG), a membrane receptor that links the cytoskeleton with the extracellular matrix in the skeletal muscle and in a variety of other tissues. LARGE1 acts by adding the repeating disaccharide unit [-3Xyl-alpha 1,3GlcA beta 1-] to the extracellular portion of the DG complex (alpha-DG); defects in the LARGE1 gene result in an aberrant glycosylation of alpha-DG and consequent impairment of its binding to laminin, eventually affecting the connection between the cell and the extracellular environment. In the skeletal muscle, this leads to degeneration of the muscular tissue and muscular dystrophy. So far, a few missense mutations have been identified within the LARGE! protein and linked to congenital muscular dystrophy, and because no structural information is available on this enzyme, our understanding of the molecular mechanisms underlying these pathologies is still very limited. Here, we generated a 3D model structure of the two catalytic domains of LARGE1, combining different molecular modeling approaches. Furthermore, by using molecular dynamics simulations, we analyzed the effect on the structure and stability of the first catalytic domain of the pathological missense mutation S331F that gives rise to a severe form of muscle-eye-brain disease.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available