Source data: PolyPR interaction with nuclear transport components

The disruption of nucleocytoplasmic transport (NCT) is an important
mechanism in neurodegenerative diseases. In the case of C9orf72-ALS,
trafficking of macromolecules through the nuclear pore complex (NPC) might
get frustrated by the binding of C9orf72-translated arginine-containing
dipeptide repeat proteins (R-DPRs) to the Kapβ family of nuclear transport
receptors. Beside Kapβs, several other types of transport components have
been linked to NCT impairments in R-DPRs expressed cells, but the
molecular origin of these observations has not been clarified. Here, we
adopt a coarse-grained molecular dynamics model at amino-acid resolution
to study the direct interaction between polyPR, the most toxic DPR, and
various nuclear transport components to elucidate the binding mechanisms
and provide a complete picture of potential polyPR-mediated NCT defects.
We found polyPR to directly bind to several isoforms of the Impα family,
CAS (the specific exporter of Impα) and RanGAP. We observe no binding
between polyPR and Ran. Longer polyPRs at lower salt concentrations also
make contact with RanGEF and NTF2. Analyzing the polyPR contact sites on
the transport components reveals that polyPR potentially interferes with
RanGTP/RanGDP binding, with nuclear localization signal (NLS)-containing
cargoes (cargo-NLS) binding to Impα, with cargo-NLS release from Impα, and
with Impα export from the nucleus. The abundance of polyPR binding sites
on multiple transport components combined with the inherent polyPR length
dependence makes direct polyPR interference of NCT a potential mechanistic
pathway of C9orf72 toxicity. The uploaded dataset provides details on the
interactions between polyPR of varying lengths and different transport
components, along with contact probabilities for individual residues.
Refer to the README file for further information.