C9orf72 polyPR directly binds to various nuclear transport components

Area of Science:

• Molecular biology
• Neuroscience
• Biophysics

Background:

• Nucleocytoplasmic transport (NCT) disruption is implicated in neurodegenerative diseases like C9orf72-associated Amyotrophic Lateral Sclerosis (ALS).
• Arginine-containing dipeptide repeat proteins (R-DPRs), translated from C9orf72, are hypothesized to interfere with NCT by binding to nuclear transport receptors, such as the Kapβ family.
• The precise molecular mechanisms underlying NCT impairments in R-DPR-expressing cells remain unclear.

Purpose of the Study:

• To investigate the direct molecular interactions between polyPR, a toxic R-DPR, and various nuclear transport components.
• To elucidate the binding mechanisms and provide a comprehensive understanding of potential polyPR-mediated defects in nucleocytoplasmic transport (NCT).
• To explore the role of these interactions in the pathogenesis of C9orf72-related neurodegeneration.

Main Methods:

• Utilized a coarse-grained molecular dynamics model at amino acid resolution.
• Simulated the direct interaction between polyPR and multiple nuclear transport factors.
• Analyzed binding sites and potential interference with transport processes.

Main Results:

• PolyPR was found to directly bind to Impα isoforms, CAS, and RanGAP.
• No binding was observed between polyPR and Ran.
• Longer polyPR chains, at lower salt concentrations, also interacted with RanGEF and NTF2.
• Analysis revealed potential interference with RanGTP/RanGDP binding, cargo-Impα interactions, and Impα nuclear export.

Conclusions:

• PolyPR directly interacts with multiple components of the nuclear pore complex (NPC) transport machinery.
• These interactions can disrupt essential NCT processes, including cargo binding and release, and nuclear export.
• The findings suggest that direct polyPR interference with NCT is a plausible mechanism contributing to C9orf72 toxicity in neurodegenerative diseases.