{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T06:24:36Z","timestamp":1787293476357,"version":"build-2736575974"},"reference-count":56,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"abstract":"<jats:p>\n                    Frataxin is a mitochondrial iron\u2010binding protein whose deficiency causes Friedreich's ataxia, yet the dynamic mechanisms by which this protein communicates iron\u2010binding events to distal regions remain poorly understood. Traditional correlation\u2010based analyses identify coupled residue motions but cannot resolve the directionality of information flow, leaving critical mechanistic gaps. Here we employ transfer entropy analysis of molecular dynamics simulations (1.5\u2009\u03bcs) to map the complete allosteric network in human frataxin, validated through orthogonal experimental approaches. We identify LEU47 (LEU136 in UniProt\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.uniprot.org\/uniprot\/Q16595\">Q16595<\/jats:ext-link>\n                    numbering) and LEU51 (LEU140) as primary signal sources with net transfer entropy values of 0.415 and 0.249, respectively, connecting the hydrophobic core to the iron\u2010binding acidic ridge. NMR relaxation at 600 and 800\u2009MHz reveals elevated R\n                    <jats:sub>2<\/jats:sub>\n                    \/R\n                    <jats:sub>1<\/jats:sub>\n                    ratios (9.90\u201310.00) and significant exchange contributions (Rex\u2009=\u20093\u20135\u2009s\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) specifically at these primary signal source residues, indicating \u03bcs\u2013ms dynamics. Hydrogen\u2013deuterium exchange mass spectrometry demonstrates that hub residues possess intermediate protection factors (ln(PF)\u2009=\u20095.97\u20136.07) optimal for conformational signaling, while iron binding induces bidirectional protection changes propagating through the identified pathway. Systematic mutagenesis confirms that disruption of hub residues reduces iron\u2010binding affinity 1.9\u20134.2\u2010fold and decreases thermal stability by 4.3\u201311.2\u2009\u00b0C, despite occupying buried\u2010core positions distant from the iron\u2010coordinating acidic\u2010ridge residues (LEU136\/LEU140 C\u03b1 to ASP122, ASP124, and GLU189\u2009=\u20096.7 to 11.8\u2009\u00c5 in PDB\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.2210\/pdb1EKG\/pdb\">1EKG<\/jats:ext-link>\n                    ). The strong prediction\u2013experiment correlation establishes transfer entropy as a reliable predictor of functionally important allosteric residues and provides a methodological framework applicable to other proteins of biomedical significance.\n                  <\/jats:p>","DOI":"10.1111\/febs.70687","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T12:25:50Z","timestamp":1786623950000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Directional information flow in human frataxin defines allosteric pathways connecting the hydrophobic core to the iron\u2010binding ridge"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2917-8860","authenticated-orcid":false,"given":"Kevser K\u00fcbra","family":"K\u0131rbo\u011fa","sequence":"first","affiliation":[{"name":"Faculty of Engineering, Department of Bioengineering Bilecik \u015eeyh Edebali University  Bilecik T\u00fcrkiye"},{"name":"Department of Bioengineering S\u00fcleyman Demirel University  Isparta T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ecir U\u011fur","family":"K\u00fc\u00e7\u00fcksille","sequence":"additional","affiliation":[{"name":"Engineering Faculty, Department of Computer Engineering S\u00fcleyman Demirel University  Isparta T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/104.3.589"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/14737175.2020.1821654"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-024-03474-6"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.271.5254.1423"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2014.09.009"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(25)00175-9"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv096"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/8587203"},{"key":"e_1_2_11_10_1","article-title":"Protein mutations and stability, a link with disease: the case study of 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