|4fdd, resolution 2.30Å ()|
|Gene:||KPNB2, MIP1, TNPO1, Transportin-1, TRN (Homo sapiens), FUS, TLS (Homo sapiens)|
|Related:|| 2qmr, 2ot8, 2h4m, 1qbk
Crystal structure of KAP beta2-PY-NLS
Mutations in the proline/tyrosine-nuclear localization signal (PY-NLS) of the Fused in Sarcoma protein (FUS) cause amyotrophic lateral sclerosis (ALS). Here we report the crystal structure of the FUS PY-NLS bound to its nuclear import receptor Karyopherinbeta2 (Kapbeta2; also known as Transportin). The FUS PY-NLS occupies the structurally invariant C-terminal arch of Kapbeta2, tracing a path similar to that of other characterized PY-NLSs. Unlike other PY-NLSs, which generally bind Kapbeta2 in fully extended conformations, the FUS peptide is atypical as its central portion forms a 2.5-turn alpha-helix. The Kapbeta2-binding epitopes of the FUS PY-NLS consist of an N-terminal PGKM hydrophobic motif, a central arginine-rich alpha-helix, and a C-terminal PY motif. ALS mutations are found almost exclusively within these epitopes. Each ALS mutation site makes multiple contacts with Kapbeta2 and mutations of these residues decrease binding affinities for Kapbeta2 (K(D) for wild-type FUS PY-NLS is 9.5 nM) up to ninefold. Thermodynamic analyses of ALS mutations in the FUS PY-NLS show that the weakening of FUS-Kapbeta2 binding affinity, the degree of cytoplasmic mislocalization, and ALS disease severity are correlated.
Structural and energetic basis of ALS-causing mutations in the atypical proline-tyrosine nuclear localization signal of the Fused in Sarcoma protein (FUS)., Zhang ZC, Chook YM, Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):12017-21. doi:, 10.1073/pnas.1207247109. Epub 2012 Jul 9. PMID:22778397
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.