{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:45:20Z","timestamp":1760060720684,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T00:00:00Z","timestamp":1758672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Alfaisal University, Riyadh, Saudi Arabia","award":["25444"],"award-info":[{"award-number":["25444"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alpha-synuclein (\u03b1-Syn) protein plays a crucial role in the pathophysiology of Parkinson\u2019s disease (PD). In the 5\u2032-untranslated regions (5\u2032-UTRs) of \u03b1-Syn, mRNA has a structured iron-responsive element (IRE) with a stem loop that regulates translation. Iron (labile as Fe2+) enhances protein synthesis rates through an IRE mRNA. This investigation aimed to describe the way in which \u03b1-Syn IRE interacts with eIF4F and establish a relationship between binding affinity and translation efficiency. The strong binding affinity of \u03b1-Syn IRE with eIF4F was demonstrated by a fluorescence-based experiment, with Ka = 8.4 \u00d7 106 M\u22121 at 25 \u00b0C. Fe2+ further increased (~three-fold) the affinity of \u03b1-Syn IRE with eIF4F, outcompeting binding with IRP1. With an increase in temperature (10\u201330 \u00b0C), Kd values increased from 35.8 \u00b1 1.6 nM to 158 \u00b1 8.7 nM for the interaction of \u03b1-Syn IRE with eIF4F; however, adding Fe2+ demonstrated significantly increased affinity throughout the same temperature range. Thermodynamic analyses demonstrated that \u03b1-Syn IRE\/eIF4F binding occurred spontaneously, with the presence of van der Waals and hydrogen bonding. Fe2+ enhanced the \u03b1-Syn IRE\/eIF4F complex\u2019s change in enthalpic and binding free energy contributions, which led to a more stable complex formation through the involvement of more hydrogen bonding. Exogenous addition of eIF4F in depleted WG or RR lysates restored \u03b1-Syn protein synthesis. Fe2+ further boosted \u03b1-Syn mRNA translation. IRP1 repressed \u03b1-Syn translation, although the addition of Fe2+ reversed this effect by boosting activator eIF4F binding and decreasing repressor IRP1 binding. These findings reveal the significance of iron in the \u03b1-synuclein mRNA regulatory process and validate its contribution as a strong enhancer of \u03b1-Syn mRNA translation.<\/jats:p>","DOI":"10.3390\/ijms26199320","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T12:15:31Z","timestamp":1758716131000},"page":"9320","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fe2+-Sensing \u03b1-Synuclein Iron-Responsive Messenger RNA\/eIF4F Complex Binding and Regulating mRNA Translation Activation and Repression"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2300-4595","authenticated-orcid":false,"given":"Mateen A.","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Life Sciences, College of Science & General Studies, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/ene.14108","article-title":"Parkinson disease","volume":"27","author":"Balestrino","year":"2020","journal-title":"Eur. 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