How do SMA-linked mutations of SMN1 lead to structural/functional deficiency of the SMA protein?

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease with dysfunctional α-motor neurons in the anterior horn of the spinal cord. SMA is caused by loss (∼95% of SMA cases) or mutation (∼5% of SMA cases) of the survival motor neuron 1 gene SMN1. As the product of SMN1, SMN is a component of the SMN complex, and is also involved in the biosynthesis of the small nuclear ribonucleoproteins (snRNPs), which play critical roles in pre-mRNA splicing in the pathogenesis of SMA. To investigate how SMA-linked mutations of SMN1 lead to structural/functional deficiency of SMN, a set of computational analysis of SMN-related structures were conducted and are described in this article. Of extraordinary interest, the structural analysis highlights three SMN residues (Asp44, Glu134 and Gln136) with SMA-linked missense mutations, which cause disruptions of electrostatic interactions for Asp44, Glu134 and Gln136, and result in three functionally deficient SMA-linked SMN mutants, Asp44Val, Glu134Lys and Gln136Glu. From the computational analysis, it is also possible that SMN’s Lys45 and Asp36 act as two electrostatic clips at the SMN-Gemin2 complex structure interface.

Biophysical Basis of Hb-S Polymerization in Red Blood Cell Sickling

“…Previous molecular dynamics simulation studies also suggest that Hb-S polymerization is favoured by inter-facial electrostatic interactions (18), and is inhibited when subjected to hypoxic (low pH environment) conditions, where the side chain of Glu6 gets neutralized and the electrostatic repulsion mechanism disappears. This molecular dynamics simulation study provides a direct support that the electrostatic repulsion mechanism, previously described in (16,19,20), is a key biophysical basis for Hb-S polymerization in RBC sickling, too.…”

“…Here, the primary impact of the sicklemia-linked E6V mutation is an electrostatic one, i.e., the removal of Glu6's negatively charged side chain, while a valine (with hydrophobic side chain) is installed at amino acid residue position 6 of Hb (1,3,4). After the retrieval of the 104 Hb structures from PDB, a set of structural electrostatic analysis was carried out as described in (16), including analysis of salt bridging (side chain alone) and hydrogen bonding (both main chain and side chain) networks. In particular, the two NMR ensembles (PDB IDs: 2M6Z and 2H35) were splitted into 40 standalone structures (16), since each NMR ensemble consists of 20 structural models.…”

“…After the retrieval of the 104 Hb structures from PDB, a set of structural electrostatic analysis was carried out as described in (16), including analysis of salt bridging (side chain alone) and hydrogen bonding (both main chain and side chain) networks. In particular, the two NMR ensembles (PDB IDs: 2M6Z and 2H35) were splitted into 40 standalone structures (16), since each NMR ensemble consists of 20 structural models. As a result, a total of 142 β-globin structural models were retrieved and extracted from PDB, as of June 18, 2019.…”

Extracting the Interfacial Electrostatic Features from Experimentally Determined Antigen and/or Antibody-Related Structures inside Protein Data Bank for Machine Learning-Based Antibody Design

“…After the 888 structures (i.e., PDB files with a total size of 753 megabytes as of February 29, 2020) were accessed and downloaded directly from the PDB website [33], a comprehensive set of electrostatic analysis was carried out as described in [34] previously, including both salt bridging and hydrogen bonding analysis for all 888 structures. Specifically, for the 14 NMR structures (with PDB IDs 1CS9, 1CT6, 1CVQ, 1CW8, 1CWZ, 1F3R, 1R21, 1S4H, 1S4J, 1TOR, 1TOS, 2MKL, 2MTW, 2RLL), an in-house python script was used to split the NMR ensemble into single NMR structural models for subsequent electrostatic analysis as described previously in [34].…”

Temperature sensitive SMA-causing point mutations lead to SMN instability, locomotor defects, and premature lethality inDrosophila

“…Previously, we 96 generated an allelic series of transgenic fly lines that express SMA-causing point mutations in an 97 otherwise Smn null mutant background (Praveen et al, 2012; Praveen et al, 2014). These animals 98 express Flag-tagged wildtype or mutant SMN from the native Smn promoter ( Fig 1A) and have 99 been used to study SMA phenotypes at the behavioral, physiological, and molecular levels (Garcia Patient data along with in vitro and in silico studies indicate that certain Tudor domain mutations 114 affect SMN protein levels, but the mechanism underlying this phenomenon remains unclear, 115 especially in vivo (Hossain and Hosen, 2019;Li, 2017;Sneha et al, 2018;Takarada et al, 2017;116 Tripsianes et al, 2011). 117…”