{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T03:40:55Z","timestamp":1782099655407,"version":"3.54.5"},"reference-count":50,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T00:00:00Z","timestamp":1665532800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Italian MIUR-PRIN 2017","award":["2017ZBBYNC"],"award-info":[{"award-number":["2017ZBBYNC"]}]},{"name":"the Italian MIUR-PRIN 2017","award":["RM12117A5BDD4AEC"],"award-info":[{"award-number":["RM12117A5BDD4AEC"]}]},{"DOI":"10.13039\/501100004271","name":"Ateneo","doi-asserted-by":"publisher","award":["2017ZBBYNC"],"award-info":[{"award-number":["2017ZBBYNC"]}],"id":[{"id":"10.13039\/501100004271","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004271","name":"Ateneo","doi-asserted-by":"publisher","award":["RM12117A5BDD4AEC"],"award-info":[{"award-number":["RM12117A5BDD4AEC"]}],"id":[{"id":"10.13039\/501100004271","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The K-homology (KH) domains are small, structurally conserved domains found in proteins of different origins characterized by a central conserved \u03b2\u03b1\u03b1\u03b2 \u201ccore\u201d and a GxxG motif in the loop between the two helices of the KH core. In the eukaryotic KHI type, additional \u03b1\u03b2 elements decorate the \u201ccore\u201d at the C-terminus. Proteins containing KH domains perform different functions and several diseases have been associated with mutations in these domains, including those in the fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein crucial for the control of RNA metabolism whose lack or mutations lead to fragile X syndrome (FXS). Among missense mutations, the R138Q substitution is in the KH0 degenerated domain lacking the classical GxxG motif. By combining equilibrium and kinetic experiments, we present a characterization of the folding mechanism of the KH0 domain from the FMRP wild-type and of the R138Q variant showing that in both cases the folding mechanism implies the accumulation of an on-pathway transient intermediate. Moreover, by exploiting a battery of biophysical techniques, we show that the KH0 domain has the propensity to form amyloid-like aggregates in mild conditions in vitro and that the R138Q mutation leads to a general destabilization of the protein and to an increased fibrillogenesis propensity.<\/jats:p>","DOI":"10.3390\/ijms232012178","type":"journal-article","created":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T20:53:29Z","timestamp":1665608009000},"page":"12178","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Folding Mechanism and Aggregation Propensity of the KH0 Domain of FMRP and Its R138Q Pathological Variant"],"prefix":"10.3390","volume":"23","author":[{"given":"Daniele","family":"Santorelli","sequence":"first","affiliation":[{"name":"Department of Biochemical Sciences \u201cA Rossi Fanelli\u201d\u2014Sapienza, University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Troilo","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Pathology National Research Council of Italy, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Fata","sequence":"additional","affiliation":[{"name":"Department of Health, Life and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Angelucci","sequence":"additional","affiliation":[{"name":"Department of Health, Life and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Demitri","sequence":"additional","affiliation":[{"name":"Elettra\u2014Sincrotrone Trieste, S.S. 14 Km 163.5, Area Science Park, Basovizza, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0802-1370","authenticated-orcid":false,"given":"Giorgio","family":"Giardina","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences \u201cA Rossi Fanelli\u201d\u2014Sapienza, University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Federici","sequence":"additional","affiliation":[{"name":"Department of Innovative Technologies in Medicine and Dentistry and Center for Advanced Studies and Technology (CAST), University of Chieti \u201cG. d\u2019Annunzio\u201d, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Catalano","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences \u201cA Rossi Fanelli\u201d\u2014Sapienza, University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5921-7365","authenticated-orcid":false,"given":"Adele","family":"Di Matteo","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Pathology National Research Council of Italy, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8735-1126","authenticated-orcid":false,"given":"Carlo","family":"Travaglini-Allocatelli","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences \u201cA Rossi Fanelli\u201d\u2014Sapienza, University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1093\/nar\/21.5.1193","article-title":"The pre-mRNA binding K protein contains a novel evolutionary conserved motif","volume":"21","author":"Siomi","year":"1993","journal-title":"Nucleic Acids Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2712","DOI":"10.1111\/j.1742-4658.2008.06411.x","article-title":"Structure and function of KH domains","volume":"275","author":"Valverde","year":"2008","journal-title":"FEBS J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.sbi.2015.01.002","article-title":"KH-RNA interactions: Back in the groove","volume":"30","author":"Nicastro","year":"2015","journal-title":"Curr. 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