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Millisecond Hydrogen/Deuterium-Exchange Mass Spectrometry for the Study of Alpha-Synuclein Structural Dynamics Under Physiological Conditions
Published on: June 23, 2022
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Structural characterization and conformational dynamics of alpha-1 antitrypsin pathogenic variants causing
Noor Ahmad Shaik1,2, Najla Bint Saud Al-Saud3, Thamer Abdulhamid Aljuhani1
1Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Frontiers in Molecular Biosciences
|December 12, 2022
Summary
Pathogenic variants in the SERPINA1 gene causing Alpha-1 antitrypsin deficiency (A1ATD) destabilize the A1AT protein structure and function. Computational analysis reveals these mutations impact protein folding and NE ligand binding, contributing to A1ATD complications.
Area of Science:
- Computational Biology
- Genetics
- Biochemistry
Background:
- Alpha-1 antitrypsin deficiency (A1ATD) is a genetic lung disorder linked to SERPINA1 gene variants.
- The precise impact of these variants on alpha-1 anti-trypsin (A1AT) protein structure and function remains incompletely understood.
Purpose of the Study:
- To computationally investigate the structural and functional consequences of pathogenic SERPINA1 missense variants.
- To elucidate the genotype-protein phenotype relationship in A1ATD.
Main Methods:
- Collected and filtered pathogenic SERPINA1 missense variants from databases.
- Constructed tertiary protein models and employed computational methods to assess variant impact on secondary structure, stability, and molecular dynamics.
- Evaluated effects on A1AT protein-ligand interactions.
Main Results:
- Identified six highly deleterious SERPINA1 variants (F76S, S77F, L278P, E288V, G216C, H358R) using multiple prediction tools.
- These variants were predicted to destabilize A1AT protein, causing minor structural drifts and altering secondary structural elements.
- Simulations confirmed damaging conformational changes and predicted impaired binding with the NE ligand.
Conclusions:
- This study provides computational insights into how SERPINA1 variants affect A1AT protein structure and function, contributing to A1ATD.
- A1ATD complications are linked to altered protein conformational flexibility and increased propensity for misfolding and polymerization.
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