Importins and NLSs

Even though there are at least 10 different Importins, NLSs are known for only a few of these systems. The classical-NLS was discovered in the 1980s and is recognized by the Importinα/Importinβ heterodimer. In 2006, we defined a new NLS class termed the PY-NLS. More recently, a Lys-rich Kap121-specicifc NLS and an RS-repeat NLS were characterized.

Using structural, biochemical and bioinformatics approaches, we defined a set of physical rules for PY-NLS recognition by Kapβ2 (also known as Transportin) and used these to discover new candidate cargos. We showed that physical characteristics, rather than sequence motifs alone, describe PY-NLS recognition. We designed the first nuclear-import inhibitor and revealed biophysical properties that govern Karyopherin-PY-NLS affinities. These discoveries allowed neuroscientists to determine that defective nuclear import of cargo FUS causes familial-ALS disease. The Chook Lab has since revealed structural/energetic basis of ALS mutations in the PY-NLS of FUS and correlated them to disease severity.