Coarse-grained models of transport components used in this study

One-bead-per-amino acid (1BPA) representation of the various transport components modeled in the current study. These are several members of the Impα family (excluding the N-terminal IBB domain), specific exporters of Impα (CAS and Cse1), RanGAP, RanGEF, NTF2, and Ran. Details regarding the CG models and protein sequences are listed in tables S2 and S3.

The transport component’s net charge per residue and dipole moment, together with polyPR length, affect polyPR interaction with various nuclear transport components

(a) and (b) show the normalized time-averaged number of contacts Ct for the interaction between polyPR with 7, 20, and 50 repeat units with different types of transport components. The results are shown for monovalent salt concentrations of Csalt = 200 mM (left panels) and Csalt = 100 mM (right panels). Subfigure (a) shows the results for the transport components shown in figure 1, excluding the specific exporters of Impα: CAS and Cse1. A linear correlation is observed between the normalized Ct and NCPR − fM/Rg with f calculated to be 0.0036 for the best fit. The net charge per residue NCPR is in units of elementary charge e, the dipole moment M is in units of e.nm, and the radius of gyration Rg is in units of nm. Subfigure (b) shows the results for the Kapβ data set (data points taken from [32]) together with CAS and Cse1. For this case, a linear correlation between Ct and NCPR is observed. The dashed lines show linear fits for PR20 and PR50. The error bars show half the standard deviation.

PolyPR interacts with several known binding sites of nuclear transport components in a length-dependent manner

(a) The contact probability for each residue in the sequence of transport components interacting with polyPR. The plot displays the contact probability for six transport components: Impα1ΔN, KAP60ΔN, Cse1, RanGAP, RanGEF and NTF2 at a salt concentration of 100 mM. Results for Impα3ΔN, Impα5ΔN, Impα7ΔN, CAS, and Ran are shown in figure S4. Each figure shows two curves for PR7 and PR50. The bottom part of each figure shows the binding sites for NLS-cargo, Impα, CAS/Cse1, RanGTP, and Nup50/Nup2 using different colors. These binding sites are obtained from the crystal structures of the bound states of transport components in the Protein Data Bank using PiSITE (see table S2 of the SI for more details). For each transport component the following binding sites are marked. For the Impα family: NLS-cargo (vertical black lines), CAS/Cse1 (vertical purple lines) and Nup50/Nup2 (vertical orange lines) binding sites. For CAS/Cse1: Impα (vertical black lines) and RanGTP (vertical green lines) binding sites. For RanGAP: RanGTP (vertical green lines) binding sites. For RanGEF: Ran (vertical green lines) binding sites. For NTF2: RanGDP (vertical green lines) binding sites. The Ran binding sites marked for RanGEF are taken from the RanGEF-Ran complex (an intermediate step in the RanGEF function).

(b) The number of shared contact sites between polyPR and the binding partners of the transport components, referred to as Nshared, are plotted for PR7, PR20, and PR50. In each bar plot, the numbers inside the parentheses on the horizontal axis shows the number of known binding sites obtained from PiSITE. If there is no known binding site, a (-) mark is used instead. The results for PR7, PR20, and PR50 are reported from left to right for each set of bar plots. The bars with darker colors represent longer polyPR chains.

Suggested molecular mechanism of polyPR interference with the native function of transport components in the nucleocytoplasmic transport cycle.

(a) Proposed mechanistic pathways of polyPR interference with the import cycle (left panel), Ran cycle (middle panel), and export cycle (right panel). Steps in the NCT cycle are represented with grey arrows, and a red dashed arrow indicates where polyPR may interfere with the transport cycle. The letters A-H are used to illustrate how polyPR may disrupt the function of the transport components. Each letter corresponds to a mechanistic mechanism shown at the bottom of the figure in grey circles. It should be noted that the proposed mechanisms are not equally significant. The relative significance of the suggested molecular mechanisms can be obtained by considering their relative contributions based on the number of contacts and the number of contacts with important binding sites as presented in figures 2 and 3, respectively.