Three-dimensional context rather than NLS amino acid sequence determines importin ? subtype specificity for RCC1.

ABSTRACT: Active nuclear import of Ran exchange factor RCC1 is mediated by importin ?3. This pathway is essential to generate a gradient of RanGTP on chromatin that directs nucleocytoplasmic transport, mitotic spindle assembly and nuclear envelope formation. Here we identify the mechanisms of importin ?3 selectivity for RCC1. We find this isoform binds RCC1 with one order of magnitude higher affinity than the generic importin ?1, although the two isoforms share an identical NLS-binding groove. Importin ?3 uses its greater conformational flexibility to wedge the RCC1 ?-propeller flanking the NLS against its lateral surface, preventing steric clashes with its Armadillo-core. Removing the ?-propeller, or inserting a linker between NLS and ?-propeller, disrupts specificity for importin ?3, demonstrating the structural context rather than NLS sequence determines selectivity for isoform 3. We propose importin ?3 evolved to recognize topologically complex NLSs that lie next to bulky domains or are masked by quaternary structures.Importin ?3 facilitates the nuclear transport of the Ran guanine nucleotide exchange factor RCC1. Here the authors reveal the molecular basis for the selectivity of RCC1 for importin ?3 vs the generic importin ?1 and discuss the evolution of importin ? isoforms.

SUBMITTER: Sankhala RS 

PROVIDER: S-EPMC5645467 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature