Artificial intelligence and the analysis of cryo-EM data provide structural insight into the molecular mechanisms underlying LN-lamininopathies

Laminins (Lm) are major components of basement membranes (BM), which polymerize to form a planar lattice on cell surface. Genetic alternations of Lm affect their oligomerization patterns and lead to failures in BM assembly manifesting in a group of human disorders collectively defined as Lm N-termin...

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Bibliographic Details
Published in:Scientific reports 2023-10, Vol.13 (1), p.17825-17825, Article 17825
Main Author: Kulczyk, Arkadiusz W.
Format: Article
Language:English
Subjects:
631/114/2397
631/535/1258/1259
Artificial intelligence
Basement membranes
Cell surface
Congenital diseases
Drug development
Humanities and Social Sciences
Molecular modelling
multidisciplinary
Muscular dystrophy
Mutation
Oligomerization
Polymerization
Polymers
Proteins
Science
Science (multidisciplinary)
Structural analysis
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Summary:Laminins (Lm) are major components of basement membranes (BM), which polymerize to form a planar lattice on cell surface. Genetic alternations of Lm affect their oligomerization patterns and lead to failures in BM assembly manifesting in a group of human disorders collectively defined as Lm N-terminal domain lamininopathies (LN-lamininopathies). We have employed a recently determined cryo-EM structure of the Lm polymer node, the basic repeating unit of the Lm lattice, along with structure prediction and modeling to systematically analyze structures of twenty-three pathogenic Lm polymer nodes implicated in human disease. Our analysis provides the detailed mechanistic explanation how Lm mutations lead to failures in Lm polymerization underlining LN-lamininopathies. We propose the new categorization scheme of LN-lamininopathies based on the insight gained from the structural analysis. Our results can help to facilitate rational drug design aiming in the treatment of Lm deficiencies.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-023-45200-5