ALS-causing mutations in profilin-1 alter its conformational dynamics: A computational approach to explain propensity...

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Profilin-1 (PFN1) is crucial for actin dynamics and has binding sites for actin and poly-L-proline (PLP).
• Eight PFN1 gene mutations are linked to amyotrophic lateral sclerosis (ALS), a motor neuron disease.
• Previous studies indicate specific mutations (G118V, C71G, Met114Thr, Thr109Met) cause ALS-like symptoms and neurotoxicity.

Purpose of the Study:

• To investigate the structural changes in PFN1 caused by ALS-associated mutations.
• To understand how these mutations affect PFN1's interactions with actin and PLP.
• To elucidate the molecular mechanisms underlying PFN1-related neurodegeneration in ALS.

Main Methods:

• Utilized molecular dynamics simulations to analyze PFN1 structure.
• Assessed alterations in secondary and tertiary structures of PFN1 mutants.
• Compared wild-type (WT) PFN1 with G118V and T109M mutants.

Main Results:

• The G118V mutation reduced loop flexibility and increased local hydrophobicity.
• The T109M mutation altered the PLP-binding site shape and decreased its flexibility.
• Simulations revealed differential fluctuation patterns and altered salt bridge/hydrogen bond formations in mutants compared to WT PFN1.

Conclusions:

• ALS-associated PFN1 mutations induce significant structural perturbations.
• Altered flexibility and binding site characteristics may lead to PFN1 misfolding and aggregation.
• These structural changes provide insights into the molecular basis of PFN1-related ALS pathogenesis.