Abstract
One of the most conserved cellular pathways among eukaryotes is the extensively studied classical protein nuclear import pathway mediated by importin-α. Classical nuclear localization signals (cNLSs) are recognized by importin-α and are highly predictable due to their abundance of basic amino acids. However, various studies in model organisms have repeatedly demonstrated that only a fraction of nuclear proteins contain identifiable cNLSs, including those that directly interact with importin-α. Using data from the Human Protein Atlas and the Human Reference Interactome, and proteomic data from BioID/protein-proximity labeling studies using multiple human importin-α proteins, we determine that nearly 50% of the human nuclear proteome does not have a predictable cNLS. Surprisingly, between 25% and 50% of previously identified human importin-α cargoes do not have predictable cNLS. Analysis of importin-α cargo without a cNLS identified an alternative basic rich motif that does not resemble a cNLS. Furthermore, several previously suspected piggybacking proteins were identified, such as those belonging to the RNA polymerase II and transcription factor II D complexes. Additionally, many components of the mediator complex interact with at least one importin-α, yet do not have a predictable cNLS, suggesting that many of the subunits may enter the nucleus through an importin-α-dependent piggybacking mechanism.
Highlights
The nucleocytoplasmic transport of proteins across the nuclear envelope is an essential cellular process unique to eukaryotic organisms
Despite the Human Reference Interactome (HuRI) dataset being relatively small compared to the number of potential nuclear proteins that may bind Imp-α, these findings demonstrate that a potentially large fraction of Imp-α binary interactions may be mediated by a non-typical Classical nuclear localization signals (cNLSs)
Our results extend previous findings found in model organisms to provide evidence that nuclear import signals are absent in a major fraction of the human nuclear proteome
Summary
The nucleocytoplasmic transport of proteins across the nuclear envelope is an essential cellular process unique to eukaryotic organisms. The transport of proteins and RNA across the nuclear envelope is a tightly orchestrated process that requires all molecules to pass through the nuclear pore complex (NPC), a large multimeric complex built from multiple copies of approximately. Proteins of varying sizes are able to diffuse through the central channel of the NPC; this is influenced by several factors. The rate at which a protein can diffuse into the nucleus is inversely related to its size. As protein size increases from
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