Effect of E134K pathogenic mutation of SMN protein on SMN-SmD1 interaction, with implication in spinal muscular atrophy: A molecular dynamics study.

Autor: Polverini E; Department of Mathematical, Physical and Computer Sciences, University of Parma, Parco Area delle Scienze 7/A, 43124 Parma, Italy. Electronic address: eugenia.polverini@unipr.it., Squeri P; Department of Chemistry, Life Science and Environmental Sustainability, University of Parma, Parco Area delle Scienze 11/A, 43124 Parma, Italy., Gherardi V; Department of Chemistry, Life Science and Environmental Sustainability, University of Parma, Parco Area delle Scienze 11/A, 43124 Parma, Italy.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2024 Aug; Vol. 275 (Pt 2), pp. 133663. Date of Electronic Publication: 2024 Jul 03.
DOI: 10.1016/j.ijbiomac.2024.133663
Abstrakt: Spinal muscular atrophy (SMA) is a disease that results from mutations in the Survival of Motor Neuron (SMN) gene 1, leading to muscle atrophy due to motor neurons degeneration. SMN plays a crucial role in the assembly of spliceosomal small nuclear ribonucleoprotein complexes via binding to the arginine-glycine rich C-terminal tails of Sm proteins recognized by SMN Tudor domain. E134K Tudor mutation, cause of the more severe type I SMA, compromises the SMN-Sm interaction without a perturbation of the domain fold. By molecular dynamics simulations, we investigated the mechanism of Tudor-SmD1 interaction, and the effects on it of E134K mutation. It was observed that E134 is crucial to catch the positive dimethylated arginines (DMRs) of the SmD1 tail that, wrapping around the acidic Tudor surface, enters a central DMR into an aromatic cage. The flexible cage residue Y130 must be blocked from the wrapped tail to assure a stable binding. The charge inversion in E134K mutation causes the loss of a critical anchor point, disfavoring the tail wrapping and leaving Y130 free to swing, leading to DMR detachments and exposition of the C-terminal region of the tail. This could suggest new hypotheses regarding a possible autoimmune response by anti-Sm autoantibodies.
Competing Interests: Declaration of competing interest Authors state no conflict of interest.
(Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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