https://m2.mtmt.hu/ hun 2026-05-25 00:46 JournalArticle 34083456 APPROVED true Institute of Enzymology, Research Centre for Natural Sciences, Budapest, 1117, Hungary Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, 1083, Hungary Export Date: 01 August 2023; Cited By: 0; Correspondence Address: I. Hajdú; Institute of Enzymology, Research Centre for Natural Sciences, Budapest, 1117, Hungary; email: hajdu.istvan@ttk.hu; P. Závodszky; Institute of Enzymology, Research Centre for Natural Sciences, Budapest, 1117, Hungary; email: zavodszky.peter@ttk.hu 0 false 2026-05-23T03:10:39.664+0000 2023-08-01T10:24:07.290+0000 2023-08-01T10:18:06.493+0000 true 10035718 Sonnevend Kinga /api/admin/10035718 Admin true 10035718 2024-04-03T10:56:31.835+0000 2024-04-03T10:56:31.835+0000 Admin 10014568 /api/admin/10014568 Vándor Andrea true 10014568 true 2024-04-04T10:41:44.202+0000 true false true 24 24 /api/publicationtype/24 PublicationType 1 true 24 JournalArticle true 10000059 Article true 24 24 /api/publicationtype/24 PublicationType 1 true 24 JournalArticle /api/subtype/10000059 Szakcikk SubType 101 true 10000059 true 1 /api/category/1 Category true 1 Hajdú, I. Beta-Secretase 1 Recruits Amyloid-Beta Precursor Protein to ROCK2 Kinase, Resulting in Erroneous Phosphorylation and Beta-Amyloid Plaque Formation true true /api/journal/10003252 REVIEWED true false 10003252 false 10003252 true 1661-6596 1422-0067 Journal FOREIGN 24 13 10416 10416 2023 The amyloidogenic processing of APP depends on two events: its phosphorylation by ROCK2 (at Thr654) and the phosphorylation of the APP-cleaving enzyme BACE1 (at Ser498). However, the mechanisms and structural details of APP-ROCK2 and BACE1-ROCK2 binding are unknown. Using direct physical methods in combination with an in silico approach, we found that BACE1 binds into the substrate-binding groove of ROCK2 with a low affinity (Kd = 18 µM), while no binding of APP to ROCK2 alone could be detected. On the other hand, a strong association (Kd = 3.5 nM) of APP to the weak ROCK2-BACE1 complex was observed, although no stable ternary complex was detected, i.e., BACE1 was displaced by APP. We constructed a sequential functional model: (1) BACE1 weakly binds to ROCK2 and induces an allosteric conformational change in ROCK2; (2) APP strongly binds to the ROCK2-BACE1 complex, and BACE1 is released; and (3) ROCK2 phosphorylates APP at Thr654 (leading to a longer stay in the early endosome during APP processing). Direct fluorescence titration experiments showed that the APP646–664 or APP665–695 fragments did not bind separately to the ROCK2-BACE1 complex. Based on these observations, we conclude that two binding sites are involved in the ROCK2-APP interaction: (1) the substrate-binding groove, where the APP646–664 sequence containing Thr654 sits and (2) the allosteric binding site, where the APP665–695 sequence binds. These results open the way to attack the allosteric site to prevent APP phosphorylation at Thr654 by ROCK2 without inhibiting the activity of ROCK2 towards its other substrates. © 2023 by the authors. 2023 true true true false false GOLD 2026-05-23 false http://www.mdpi.com/journal/ijms 3 0 3 3 0 3 3 3 2 3 3 3 3 3 0 0 3 3 3 3 0 2 2 Folyóiratcikk Journal Article 24 3 Könyvrészlet Chapter in Book 25 0 Könyv Book 23 0 Egyéb konferenciaközlemény Conference paper 31 0 Egyéb konferenciakötet Conference proceedings 32 0 Oltalmi formák Protection forms 26 0 Disszertáció Thesis 28 0 Egyéb Miscellaneous 29 0 Alkotás Achievement 22 0 Kutatási adat Research data 33 0 Folyóiratcikk Journal Article 24 0 0 0 Könyvrészlet Chapter in Book 25 0 0 0 Könyv Book 23 0 0 0 Egyéb konferenciaközlemény Conference paper 31 0 0 0 Egyéb konferenciakötet Conference proceedings 32 0 0 0 Oltalmi formák Protection forms 26 0 0 0 Disszertáció Thesis 28 0 0 0 Egyéb Miscellaneous 29 0 0 0 Alkotás Achievement 22 0 0 0 Kutatási adat Research data 33 0 0 0 2024 0 1 1 1 1 2025 0 2 2 2 2 D1 false 10010376 false false false 2023-10-30T11:24:06.927+0000 Enzimológiai Intézet (TTK); Információs Technológiai és Bionikai Kar (PPKE) 4 22 2 4 0 true 10014568 Language 10002 /api/language/10002 Angol English true 2 true PersonAuthorship 109487547 /api/authorship/109487547 1 0.25 true false false Author 10015238 /api/author/10015238 Hajdú István true 10015238 true Hajdú I. true false false AuthorshipType 1 /api/authorshiptype/1 0 true 0 true false true PersonAuthorship 109487548 /api/authorship/109487548 2 0.25 false false false Author 10018761 /api/author/10018761 Végh Barbara true 10018761 true Végh B.M. true false false AuthorshipType 1 /api/authorshiptype/1 0 true 0 true false true PersonAuthorship 109487549 /api/authorship/109487549 3 0.25 false false false Author 10010376 /api/author/10010376 Szilágyi András true 10010376 true Szilágyi A. true false false AuthorshipType 1 /api/authorshiptype/1 0 true 0 true false true PersonAuthorship 109487550 /api/authorship/109487550 4 0.25 false true false Author 10000346 /api/author/10000346 Závodszky Péter true 10000346 true Závodszky P. true false false AuthorshipType 1 /api/authorshiptype/1 0 true 0 true false true PublicationIdentifier 24222561 /api/publicationidentifier/24222561 PlainSource 6 /api/publicationsource/6 PublicationSourceType 10001 /api/publicationsourcetype/10001 true true true DOI DOI https://doi.org/@@@ true true 6 true IDENTICAL 10.3390/ijms241310416 https://doi.org/10.3390/ijms241310416 false true PublicationIdentifier 24422897 /api/publicationidentifier/24422897 PlainSource 1 /api/publicationsource/1 PublicationSourceType 10003 /api/publicationsourcetype/10003 false true true WoS WoS https://www.webofscience.com/wos/woscc/full-record/@@@ true true 1 true IDENTICAL 001032969000001 https://www.webofscience.com/wos/woscc/full-record/001032969000001 false true PublicationIdentifier 24222560 /api/publicationidentifier/24222560 PlainSource 3 /api/publicationsource/3 PublicationSourceType 10003 /api/publicationsourcetype/10003 false true true Scopus Scopus http://www.scopus.com/record/display.url?origin=inward&eid=2-s2.0-@@@ true true 3 true IDENTICAL 85164846724 http://www.scopus.com/record/display.url?origin=inward&eid=2-s2.0-85164846724 false true Keyword 65 /api/keyword/65 true 65 true Keyword 81 /api/keyword/81 true 81 true Keyword 81 /api/keyword/81 true 81 true Keyword 81 /api/keyword/81 true 81 true Keyword 334 /api/keyword/334 true 334 true Keyword 3122 /api/keyword/3122 true 3122 true Keyword 12637 /api/keyword/12637 true 12637 true Keyword 1009611 /api/keyword/1009611 true 1009611 true Keyword 1009611 /api/keyword/1009611 true 1009611 true Keyword 1033034 /api/keyword/1033034 true 1033034 true Keyword 1033150 /api/keyword/1033150 true 1033150 true Keyword 1047376 /api/keyword/1047376 true 1047376 true Keyword 1065774 /api/keyword/1065774 true 1065774 true Keyword 1088580 /api/keyword/1088580 true 1088580 true Keyword 1115202 /api/keyword/1115202 true 1115202 true Keyword 1174880 /api/keyword/1174880 true 1174880 true Keyword 1220426 /api/keyword/1220426 true 1220426 true Keyword 1266489 /api/keyword/1266489 true 1266489 true Keyword 1495684 /api/keyword/1495684 true true Keyword 1514819 /api/keyword/1514819 true true Keyword 1563194 /api/keyword/1563194 true true Keyword 2154068 /api/keyword/2154068 true true Keyword 2537691 /api/keyword/2537691 true true Keyword 2825057 /api/keyword/2825057 true true Keyword 3138314 /api/keyword/3138314 true true SjrRating 11388415 /api/sjrrating/11388415 7 0.1 journal RatingType 10002 /api/ratingtype/10002 sjr true true ClassificationExternal 1604 /api/classificationexternal/1604 true 1604 true D1 DIRECT true true /api/publication/34083456 <div class="JournalArticle Publication long-list"> <div class="authors"> <img title="Forrásközlemény" style="float: left" src="/frontend/resources/grid/publication-core-icon.png"> <img title="Idézőközlemény" style="float: left" src="/frontend/resources/grid/publication-citation-icon.png"> <div class="autype autype0"> <span class="author-name" mtid="10015238"><a href="/gui2/?type=authors&mode=browse&sel=10015238" target="_blank">Hajdú I. (<span class="authorship-author-name">Hajdú István</span> <span class="authorAux-mtmt"> Biofizika, Biokémia</span>) </a> </span> <span class="author-affil"><span title="Természettudományi Kutatóközpont">TTK</span>/Enzimológiai Intézet</span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" mtid="10018761"><a href="/gui2/?type=authors&mode=browse&sel=10018761" target="_blank">Végh B.M. (<span class="authorship-author-name">Végh Barbara</span> <span class="authorAux-mtmt"> </span>) </a> </span> <span class="author-affil"><span title="Természettudományi Kutatóközpont">TTK</span>/Enzimológiai Intézet</span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" mtid="10010376"><a href="/gui2/?type=authors&mode=browse&sel=10010376" target="_blank">Szilágyi A. (<span class="authorship-author-name">Szilágyi András</span> <span class="authorAux-mtmt"> Bioinformatika</span>) </a> </span> <span class="author-affil"><span title="Természettudományi Kutatóközpont">TTK</span>/Enzimológiai Intézet</span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" mtid="10000346"><a href="/gui2/?type=authors&mode=browse&sel=10000346" target="_blank">Závodszky P. (<span class="authorship-author-name">Závodszky Péter</span> <span class="authorAux-mtmt"> Molekuláris immunológia, biokémia</span>) </a> </span> <span class="author-affil"><span title="Természettudományi Kutatóközpont">TTK</span>/Enzimológiai Intézet; <span title="Pázmány Péter Katolikus Egyetem">PPKE</span>/Információs Technológiai és Bionikai Kar</span> </div> </div> <div class="title"><a href="/gui2/?mode=browse&params=publication;34083456" target="_blank">Beta-Secretase 1 Recruits Amyloid-Beta Precursor Protein to ROCK2 Kinase, Resulting in Erroneous Phosphorylation and Beta-Amyloid Plaque Formation</a></div> <div> <span class="journal-title">INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES</span> <span class="journal-issn">(<a target="_blank" href="https://portal.issn.org/resource/ISSN/1661-6596">1661-6596</a> <a target="_blank" href="https://portal.issn.org/resource/ISSN/1422-0067">1422-0067</a>)</span>: <span class="journal-volume">24</span> <span class="journal-issue">13</span> <span class="page"> Paper 10416. </span> <span class="year">(2023)</span> </div> <div class="pub-footer"> <span class="language" xmlns="http://www.w3.org/1999/html">Nyelv: Angol | </span> <span class="identifiers"> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="10.3390/ijms241310416" target="_blank" href="https://doi.org/10.3390/ijms241310416"> DOI </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="001032969000001" target="_blank" href="https://www.webofscience.com/wos/woscc/full-record/001032969000001"> WoS </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="85164846724" target="_blank" href="http://www.scopus.com/record/display.url?origin=inward&eid=2-s2.0-85164846724"> Scopus </a> </span> </span> <OnlyViewableByAuthor><div class="ratings"> <div class="journal-subject">Folyóirat szakterülete: Scopus - Inorganic Chemistry&nbsp;&nbsp;&nbsp;SJR indikátor:&nbsp;D1</div> <div class="journal-subject">Folyóirat szakterülete: Scopus - Organic Chemistry&nbsp;&nbsp;&nbsp;SJR indikátor:&nbsp;D1</div> <div class="journal-subject">Folyóirat szakterülete: Scopus - Spectroscopy&nbsp;&nbsp;&nbsp;SJR indikátor:&nbsp;D1</div> <div class="journal-subject">Folyóirat szakterülete: Scopus - Computer Science Applications&nbsp;&nbsp;&nbsp;SJR indikátor:&nbsp;Q1</div> <div class="journal-subject">Folyóirat szakterülete: Scopus - Medicine (miscellaneous)&nbsp;&nbsp;&nbsp;SJR indikátor:&nbsp;Q1</div> <div class="journal-subject">Folyóirat szakterülete: Scopus - Physical and Theoretical Chemistry&nbsp;&nbsp;&nbsp;SJR indikátor:&nbsp;Q1</div> <div class="journal-subject">Folyóirat szakterülete: Scopus - Catalysis&nbsp;&nbsp;&nbsp;SJR indikátor:&nbsp;Q2</div> <div class="journal-subject">Folyóirat szakterülete: Scopus - Molecular Biology&nbsp;&nbsp;&nbsp;SJR indikátor:&nbsp;Q2</div> </div></OnlyViewableByAuthor> <div class="publication-citation" style="margin-left: 0.5cm;"> <span title="Nyilvános idézőközlemények összesen, említések nélkül" class="citingPub-count">Nyilvános idéző összesen: 3</span> | Független: 3 | Függő: 0 | Nem jelölt: 0 | WoS jelölt: 3 | Scopus jelölt:&nbsp;2 | WoS/Scopus jelölt:&nbsp;3 | DOI jelölt:&nbsp;3 </div> <div class="publication-citation"> <a target="_blank" href="/api/publication?cond=citations.related;eq;34083456&sort=publishedYear,desc&sort=title"> Idézett közlemények száma: 2 </a> </div> <div class="mtid"><span class="long-pub-mtid">Közlemény: 34083456</span> | <span class="status-data status-APPROVED"> Nyilvános </span> Forrás Idéző | <span class="type-subtype">Folyóiratcikk ( Szakcikk ) </span> | <span class="pub-category">Tudományos</span> | <span class="publication-sourceOfData">Scopus</span> </div> <div class="lastModified">Utolsó módosítás: 2023.08.01. 12:24 Sonnevend Kinga (SE_AOK_Adm5_Élet_kutcsop, admin) </div> <div class="lockedBy">Központi kezelésű 2024.04.04. 12:41 Vándor Andrea (VA, admin) </div> <pre class="comment" style="margin-top: 0; margin-bottom: 0;"><u>Megjegyzés</u>: Institute of Enzymology, Research Centre for Natural Sciences, Budapest, 1117, Hungary Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, 1083, Hungary Export Date: 01 August 2023; Cited By: 0; Correspondence Address: I. Hajdú; Institute of Enzymology, Research Centre for Natural Sciences, Budapest, 1117, H...</pre> </div></div>