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Traffic Rules for nuclear import pathways: Karyopherin beta2 and Kap104p
Author(s) -
Chook Yuh Min
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1038-c
Subject(s) - nls , nuclear localization sequence , nuclear transport , importin , karyopherin , computational biology , biology , nucleus , biochemistry , chemistry , microbiology and biotechnology , cell nucleus
Proteomic studies show 40% of yeast proteins enter the nucleus. By analogy, >10,000 human proteins will enter the nucleus. This huge protein traffic is mediated by 10 different import‐Kapbeta2 (Importin‐betas), each selectively binding a set of substrates by recognizing specific NLSs. Structural and biochemical analyses of Kapbeta2/Transportin bound to the NLS of hnRNP A1 have led to formulation of 3 rules for NLS recognition by Kapbeta2: NLSs are structurally disordered in free substrates, have overall basic character, and possess a central hydrophobic or basic motif followed by a R/H/KX(2–5)PY consensus sequence. These rules identified NLSs in 7 previously known Kapbeta2 substrates and bioinformatics analysis uncovered 81 new candidate substrates. These studies define and validate a new NLS termed the PY‐NLS, which could not be predicted by primary sequence analysis alone. PY‐NLSs are divided into hydrophobic or hPY‐NLSs and basic or bPY‐NLSs based on their diverse central motifs. In the structure of Kapbeta2 bound to the bPY‐NLS of hnRNP M, three‐dimensional coincidence of the central basic/hydrophobic and the C‐terminal R/H/KX(2–5)PY motifs provide structural evidence for their importance, conservation and thus their designation as consensus sequences. Comparative structural analysis also reveals the origin of recognition of diverse PY‐NLS sequences. Furthermore, structural and thermodynamic analyses of Kapbeta2‐NLS interactions have led to the design of a pathway‐selective nuclear import inhibitor. Finally, we have validated and refined the human Kapbeta2 NLS rules for the orthologous Kap104p pathway in S. cerevisiae where the rules have identified >100 new Kap104 ligands. This near‐complete traffic map of a single nuclear import pathway in yeast allows for bioinformatics analysis to explore potential functional linkages in nuclear trafficking.