{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T23:16:55Z","timestamp":1790378215733,"version":"4.1.0"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"11","license":[{"start":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T00:00:00Z","timestamp":1599091200000},"content-version":"vor","delay-in-days":184,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK-029023"],"award-info":[{"award-number":["DK-029023"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,3,17]]},"abstract":"<jats:p>\n                    Human profilin I reduces aggregation and concomitant toxicity of the polyglutamine-containing N-terminal region of the huntingtin protein encoded by exon 1 (htt\n                    <jats:sup>ex1<\/jats:sup>\n                    ) and responsible for Huntington\u2019s disease. Here, we investigate the interaction of profilin with htt\n                    <jats:sup>ex1<\/jats:sup>\n                    using NMR techniques designed to quantitatively analyze the kinetics and equilibria of chemical exchange at atomic resolution, including relaxation dispersion, exchange-induced shifts, and lifetime line broadening. We first show that the presence of two polyproline tracts in htt\n                    <jats:sup>ex1<\/jats:sup>\n                    , absent from a shorter huntingtin variant studied previously, modulates the kinetics of the transient branched oligomerization pathway that precedes nucleation, resulting in an increase in the populations of the on-pathway helical coiled-coil dimeric and tetrameric species (\u03c4\n                    <jats:sub>ex<\/jats:sub>\n                    \u2264 50 to 70 \u03bcs), while leaving the population of the off-pathway (nonproductive) dimeric species largely unaffected (\u03c4\n                    <jats:sub>ex<\/jats:sub>\n                    \u223c750 \u03bcs). Next, we show that the affinity of a single molecule of profilin to the polyproline tracts is in the micromolar range (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>diss<\/jats:sub>\n                    \u223c 17 and \u223c 31 \u03bcM), but binding of a second molecule of profilin is negatively cooperative, with the affinity reduced \u223c11-fold. The lifetime of a 1:1 complex of htt\n                    <jats:sup>ex1<\/jats:sup>\n                    with profilin, determined using a shorter huntingtin variant containing only a single polyproline tract, is shown to be on the submillisecond timescale (\n                    <jats:italic>\u03c4<\/jats:italic>\n                    <jats:sub>ex<\/jats:sub>\n                    \u223c 600 \u03bcs and\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>diss<\/jats:sub>\n                    \u223c 50 \u03bcM). Finally, we demonstrate that, in stable profilin\u2013htt\n                    <jats:sup>ex1<\/jats:sup>\n                    complexes, the productive oligomerization pathway, leading to the formation of helical coiled-coil htt\n                    <jats:sup>ex1<\/jats:sup>\n                    tetramers, is completely abolished, and only the pathway resulting in \u201cnonproductive\u201d dimers remains active, thereby providing a mechanistic basis for how profilin reduces aggregation and toxicity of htt\n                    <jats:sup>ex1<\/jats:sup>\n                    .\n                  <\/jats:p>","DOI":"10.1073\/pnas.1922264117","type":"journal-article","created":{"date-parts":[[2020,3,3]],"date-time":"2020-03-03T16:45:12Z","timestamp":1583253912000},"page":"5844-5852","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":33,"title":["Abrogation of prenucleation, transient oligomerization of the Huntingtin exon 1 protein by human profilin I"],"prefix":"10.1073","volume":"117","author":[{"given":"Alberto","family":"Ceccon","sequence":"first","affiliation":[{"name":"Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitali","family":"Tugarinov","sequence":"additional","affiliation":[{"name":"Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolfo","family":"Ghirlando","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0540"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Marius","family":"Clore","sequence":"additional","affiliation":[{"name":"Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2020,3,3]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1111\/j.1469-1809.2006.00335.x","article-title":"The relationship between CAG repeat length and age of onset differs for Huntington\u2019s disease patients with juvenile onset or adult onset","volume":"71","author":"Andresen J. M.","year":"2007","unstructured":"J. M. Andresen .; US\u2013Venezuela Collaborative Research Group; HD MAPS Collaborative Research Group, The relationship between CAG repeat length and age of onset differs for Huntington\u2019s disease patients with juvenile onset or adult onset. Ann. Hum. Genet. 71, 295\u2013301 (2007).","journal-title":"Ann. Hum. Genet."},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"15005","DOI":"10.1038\/nrdp.2015.5","article-title":"Huntington disease","volume":"1","author":"Bates G. P.","year":"2015","unstructured":"G. P. Bates ., Huntington disease. Nat. Rev. Dis. Primers 1, 15005 (2015).","journal-title":"Nat. Rev. Dis. Primers"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"10855","DOI":"10.1074\/jbc.M804813200","article-title":"Mutant huntingtin N-terminal fragments of specific size mediate aggregation and toxicity in neuronal cells","volume":"284","author":"Ratovitski T.","year":"2009","unstructured":"T. Ratovitski ., Mutant huntingtin N-terminal fragments of specific size mediate aggregation and toxicity in neuronal cells. J. Biol. Chem. 284, 10855\u201310867 (2009).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1038\/s41598-017-01510-z","article-title":"The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington\u2019s disease patients","volume":"7","author":"Neueder A.","year":"2017","unstructured":"A. Neueder ., The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington\u2019s disease patients. Sci. Rep. 7, 1307 (2017).","journal-title":"Sci. Rep."},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1093\/hmg\/ddu504","article-title":"Comparative study of naturally occurring huntingtin fragments in Drosophila points to exon 1 as the most pathogenic species in Huntington\u2019s disease","volume":"24","author":"Barbaro B. A.","year":"2015","unstructured":"B. A. Barbaro ., Comparative study of naturally occurring huntingtin fragments in Drosophila points to exon 1 as the most pathogenic species in Huntington\u2019s disease. Hum. Mol. Genet. 24, 913\u2013925 (2015).","journal-title":"Hum. Mol. Genet."},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"2767","DOI":"10.1021\/cb500335w","article-title":"Super-resolution fluorescence of huntingtin reveals growth of globular species into short fibers and coexistence of distinct aggregates","volume":"9","author":"Duim W. C.","year":"2014","unstructured":"W. C. Duim, Y. Jiang, K. Shen, J. Frydman, W. E. Moerner, Super-resolution fluorescence of huntingtin reveals growth of globular species into short fibers and coexistence of distinct aggregates. ACS Chem. Biol. 9, 2767\u20132778 (2014).","journal-title":"ACS Chem. Biol."},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"4604","DOI":"10.1073\/pnas.96.8.4604","article-title":"Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: Implications for Huntington\u2019s disease pathology","volume":"96","author":"Scherzinger E.","year":"1999","unstructured":"E. Scherzinger ., Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: Implications for Huntington\u2019s disease pathology. Proc. Natl. Acad. Sci. U.S.A. 96, 4604\u20134609 (1999).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.neuron.2016.02.003","article-title":"The biology of huntingtin","volume":"89","author":"Saudou F.","year":"2016","unstructured":"F. Saudou, S. Humbert, The biology of huntingtin. Neuron 89, 910\u2013926 (2016).","journal-title":"Neuron"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"6653","DOI":"10.1021\/bi501010q","article-title":"Polyglutamine amyloid core boundaries and flanking domain dynamics in huntingtin fragment fibrils determined by solid-state nuclear magnetic resonance","volume":"53","author":"Hoop C. L.","year":"2014","unstructured":"C. L. Hoop ., Polyglutamine amyloid core boundaries and flanking domain dynamics in huntingtin fragment fibrils determined by solid-state nuclear magnetic resonance. Biochemistry 53, 6653\u20136666 (2014).","journal-title":"Biochemistry"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"3942","DOI":"10.1021\/acs.biochem.5b00281","article-title":"Solid-state nuclear magnetic resonance on the static and dynamic domains of huntingtin exon-1 fibrils","volume":"54","author":"Isas J. M.","year":"2015","unstructured":"J. M. Isas, R. Langen, A. B. Siemer, Solid-state nuclear magnetic resonance on the static and dynamic domains of huntingtin exon-1 fibrils. Biochemistry 54, 3942\u20133949 (2015).","journal-title":"Biochemistry"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1073\/pnas.1521933113","article-title":"Huntingtin exon 1 fibrils feature an interdigitated \u03b2-hairpin-based polyglutamine core","volume":"113","author":"Hoop C. L.","year":"2016","unstructured":"C. L. Hoop ., Huntingtin exon 1 fibrils feature an interdigitated \u03b2-hairpin-based polyglutamine core. Proc. Natl. Acad. Sci. U.S.A. 113, 1546\u20131551 (2016).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"15462","DOI":"10.1038\/ncomms15462","article-title":"Fibril polymorphism affects immobilized non-amyloid flanking domains of huntingtin exon1 rather than its polyglutamine core","volume":"8","author":"Lin H. K.","year":"2017","unstructured":"H. K. Lin ., Fibril polymorphism affects immobilized non-amyloid flanking domains of huntingtin exon1 rather than its polyglutamine core. Nat. Commun. 8, 15462 (2017).","journal-title":"Nat. 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U.S.A."},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"6199","DOI":"10.1021\/jacs.8b02619","article-title":"Interaction of huntingtin exon-1 peptides with lipid-based micellar nanoparticles probed by solution NMR and Q-band pulsed EPR","volume":"140","author":"Ceccon A.","year":"2018","unstructured":"A. Ceccon ., Interaction of huntingtin exon-1 peptides with lipid-based micellar nanoparticles probed by solution NMR and Q-band pulsed EPR. J. Am. Chem. Soc. 140, 6199\u20136202 (2018).","journal-title":"J. Am. Chem. Soc."},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1177\/1073858410390378","article-title":"Small changes, big impact: Posttranslational modifications and function of huntingtin in Huntington disease","volume":"17","author":"Ehrnhoefer D. E.","year":"2011","unstructured":"D. E. Ehrnhoefer, L. Sutton, M. R. Hayden, Small changes, big impact: Posttranslational modifications and function of huntingtin in Huntington disease. 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