Crystal structure of KAP beta2-PY-NLS
[FUS_HUMAN] Frontotemporal dementia with motor neuron disease;Hereditary essential tremor;Amyotrophic lateral sclerosis;Juvenile amyotrophic lateral sclerosis;Myxofibrosarcoma;Myxoid/round cell liposarcoma. A chromosomal aberration involving FUS is found in a patient with malignant myxoid liposarcoma. Translocation t(12;16)(q13;p11) with DDIT3. A chromosomal aberration involving FUS is a cause of acute myeloid leukemia (AML). Translocation t(16;21)(p11;q22) with ERG. The disease may be caused by mutations affecting the gene represented in this entry. A chromosomal aberration involving FUS is found in a patient with angiomatoid fibrous histiocytoma. Translocation t(12;16)(q13;p11.2) with ATF1 generates a chimeric FUS/ATF1 protein. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
[TNPO1_HUMAN] Functions in nuclear protein import as nuclear transport receptor. Serves as receptor for nuclear localization signals (NLS) in cargo substrates. Is thought to mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to the importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus (By similarity). Involved in nuclear import of M9-containing proteins. In vitro, binds directly to the M9 region of the heterogeneous nuclear ribonucleoproteins (hnRNP), A1 and A2 and mediates their nuclear import. Appears also to be involved in hnRNP A1/A2 nuclear export. Mediates the nuclear import of ribosomal proteins RPL23A, RPS7 and RPL5. Binds to a beta-like import receptor binding (BIB) domain of RPL23A. In vitro, mediates nuclear import of H2A, H2B, H3 and H4 histones, and SRP19. In case of HIV-1 infection, binds and mediates the nuclear import of HIV-1 Rev. Mediates nuclear import of ADAR/ADAR1 (isoform 5) in a RanGTP-dependent manner.    [FUS_HUMAN] Binds both single-stranded and double-stranded DNA and promotes ATP-independent annealing of complementary single-stranded DNAs and D-loop formation in superhelical double-stranded DNA. May play a role in maintenance of genomic integrity.
Publication Abstract from PubMed
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.