{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T02:40:25Z","timestamp":1791513625385,"version":"4.3.4"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"30","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,7,24]]},"abstract":"<jats:p>\n                    Mutations in the proline\/tyrosine\u2013nuclear 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 Karyopherin\u03b22 (Kap\u03b22; also known as Transportin). The FUS PY-NLS occupies the structurally invariant C-terminal arch of Kap\u03b22, tracing a path similar to that of other characterized PY-NLSs. Unlike other PY-NLSs, which generally bind Kap\u03b22 in fully extended conformations, the FUS peptide is atypical as its central portion forms a 2.5-turn \u03b1-helix. The Kap\u03b22-binding epitopes of the FUS PY-NLS consist of an N-terminal PGKM hydrophobic motif, a central arginine-rich \u03b1-helix, and a C-terminal PY motif. ALS mutations are found almost exclusively within these epitopes. Each ALS mutation site makes multiple contacts with Kap\u03b22 and mutations of these residues decrease binding affinities for Kap\u03b22 (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>D<\/jats:sub>\n                    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-Kap\u03b22 binding affinity, the degree of cytoplasmic mislocalization, and ALS disease severity are correlated.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1207247109","type":"journal-article","created":{"date-parts":[[2012,7,10]],"date-time":"2012-07-10T07:59:01Z","timestamp":1341907141000},"page":"12017-12021","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":146,"title":["Structural and energetic basis of ALS-causing mutations in the atypical proline\u2013tyrosine nuclear localization signal of the Fused in Sarcoma protein (FUS)"],"prefix":"10.1073","volume":"109","author":[{"given":"Zi Chao","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuh Min","family":"Chook","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,7,9]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.cell.2006.05.049","article-title":"Rules for nuclear localization sequence recognition by karyopherin beta 2","volume":"126","author":"Lee BJ","year":"2006","unstructured":"BJ Lee, et al., Rules for nuclear localization sequence recognition by karyopherin beta 2. Cell 126, 543\u2013558 (2006).","journal-title":"Cell"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.1038\/emboj.2010.143","article-title":"ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import","volume":"29","author":"Dormann D","year":"2010","unstructured":"D Dormann, et al., ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J 29, 2841\u20132857 (2010).","journal-title":"EMBO J"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1126\/science.1166066","article-title":"Mutations in the FUS\/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis","volume":"323","author":"Kwiatkowski TJ","year":"2009","unstructured":"TJ Kwiatkowski, et al., Mutations in the FUS\/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323, 1205\u20131208 (2009).","journal-title":"Science"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1126\/science.1165942","article-title":"Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6","volume":"323","author":"Vance C","year":"2009","unstructured":"C Vance, et al., Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323, 1208\u20131211 (2009).","journal-title":"Science"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.tins.2011.05.002","article-title":"TDP-43 and FUS: A nuclear affair","volume":"34","author":"Dormann D","year":"2011","unstructured":"D Dormann, C Haass, TDP-43 and FUS: A nuclear affair. Trends Neurosci 34, 339\u2013348 (2011).","journal-title":"Trends Neurosci"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.1093\/nar\/gkq1162","article-title":"Intracellular localization and splicing regulation of FUS\/TLS are variably affected by amyotrophic lateral sclerosis-linked mutations","volume":"39","author":"Kino Y","year":"2011","unstructured":"Y Kino, et al., Intracellular localization and splicing regulation of FUS\/TLS are variably affected by amyotrophic lateral sclerosis-linked mutations. Nucleic Acids Res 39, 2781\u20132798 (2011).","journal-title":"Nucleic Acids Res"},{"key":"e_1_3_4_7_2","first-page":"e2327","article-title":"Nuclear localization sequence of FUS and induction of stress granules by ALS mutants","volume":"32","author":"Gal J","year":"2011","unstructured":"J Gal, et al., Nuclear localization sequence of FUS and induction of stress granules by ALS mutants. Neurobiol Aging 32, e2327\u2013e2340 (2011).","journal-title":"Neurobiol Aging"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1002\/ana.22246","article-title":"Nuclear transport impairment of amyotrophic lateral sclerosis-linked mutations in FUS\/TLS","volume":"69","author":"Ito D","year":"2011","unstructured":"D Ito, M Seki, Y Tsunoda, H Uchiyama, N Suzuki, Nuclear transport impairment of amyotrophic lateral sclerosis-linked mutations in FUS\/TLS. Ann Neurol 69, 152\u2013162 (2011).","journal-title":"Ann Neurol"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"4160","DOI":"10.1093\/hmg\/ddq335","article-title":"Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules","volume":"19","author":"Bosco DA","year":"2010","unstructured":"DA Bosco, et al., Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum Mol Genet 19, 4160\u20134175 (2010).","journal-title":"Hum Mol Genet"},{"key":"e_1_3_4_10_2","first-page":"765","article-title":"FUS mutations in frontotemporal lobar degeneration with amyotrophic lateral sclerosis","volume":"22","author":"Broustal O","year":"2010","unstructured":"O Broustal, et al., FUS mutations in frontotemporal lobar degeneration with amyotrophic lateral sclerosis. J Alzheimers Dis; French Clinical and Genetic Research Network on FTD\/FTD-MND 22, 765\u2013769 (2010).","journal-title":"J Alzheimers Dis"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/S1474-4422(10)70195-2","article-title":"TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia","volume":"9","author":"Mackenzie IR","year":"2010","unstructured":"IR Mackenzie, R Rademakers, M Neumann, TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. 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