{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T02:02:43Z","timestamp":1784772163508,"version":"3.55.0"},"reference-count":55,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T00:00:00Z","timestamp":1729728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Heterozygous mutations or genetic variants in the GBA1 gene, which encodes for the \u03b2-glucocerebrosidase (GCase), a lysosomal hydrolase enzyme, may increase the risk of Parkinson\u2019s disease (PD) onset. The heterozygous E326K form is one of the most common genetic risk factors for PD worldwide, but, to date, the underlying molecular mechanisms remain unclear. Here, we investigate the effect of the E326K on the structure, stability, dimerization process, and interaction mode with some proteins of the interactome of GCase using multiple molecular dynamics (MD) simulations at pH 5.5 and pH 7.0 to mimic the lysosomal and endoplasmic reticulum environments, respectively. The analysis of the MD trajectories highlights that the E326K mutation did not significantly alter the structural conformation of the catalytic dyad but significantly makes the structure of the dimeric complexes unstable, especially at lysosomal pH, potentially impacting the organization of the quaternary structure. Furthermore, the E326K mutation significantly impacts protein interactions by altering the binding mode with the activator Saposin C (SapC), reducing the binding affinity with the inhibitor \u03b1-Synuclein (\u03b1-Syn), and increasing the affinity for the Lysosomal integral membrane protein-2 (LIMP-2) transporter.<\/jats:p>","DOI":"10.3390\/ijms252111443","type":"journal-article","created":{"date-parts":[[2024,10,25]],"date-time":"2024-10-25T03:46:04Z","timestamp":1729827964000},"page":"11443","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Investigating the Impact of the Parkinson\u2019s-Associated GBA1 E326K Mutation on \u03b2-Glucocerebrosidase Dimerization and Interactome Dynamics Through an In Silico Approach"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-5154-6154","authenticated-orcid":false,"given":"Davide","family":"Pietrafesa","sequence":"first","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy"},{"name":"PhD Program in Materials for Health, Environment and Energy, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Casamassa","sequence":"additional","affiliation":[{"name":"Cellular Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini 1, 71013 San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6570-4434","authenticated-orcid":false,"given":"Barbara","family":"Benassi","sequence":"additional","affiliation":[{"name":"Division of Biotechnologies, Department for Sustainability, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Via Anguillarese 301, 00123 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Santoro","sequence":"additional","affiliation":[{"name":"Division of Biotechnologies, Department for Sustainability, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Via Anguillarese 301, 00123 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9885-3666","authenticated-orcid":false,"given":"Massimo","family":"Marano","sequence":"additional","affiliation":[{"name":"Unit of Neurology, Neurophysiology, Neurobiology and Psychiatry, Department of Medicine, University Campus Biomedico, Via Alvaro del Portillo 200, 00128 Rome, Italy"},{"name":"Fondazione Policlinico Universitario Campus Biomedico, Via Alvaro del Portillo 200, 00128 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7805-4493","authenticated-orcid":false,"given":"Claudia","family":"Consales","sequence":"additional","affiliation":[{"name":"Division of Biotechnologies, Department for Sustainability, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Via Anguillarese 301, 00123 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4483-386X","authenticated-orcid":false,"given":"Jessica","family":"Rosati","sequence":"additional","affiliation":[{"name":"Cellular Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini 1, 71013 San Giovanni Rotondo, Italy"},{"name":"Departmental Faculty of Medicine, UniCamillus, Saint Camillus International University of Health Sciences, Via di Sant\u2019Alessandro 8, 00131 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5459-1024","authenticated-orcid":false,"given":"Caterina","family":"Arcangeli","sequence":"additional","affiliation":[{"name":"Division of Biotechnologies, Department for Sustainability, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Via Anguillarese 301, 00123 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1093\/qjmed\/89.9.691","article-title":"Occurrence of Parkinson\u2019s Syndrome in Type 1 Gaucher Disease","volume":"89","author":"Neudorfer","year":"1996","journal-title":"QJM"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/S1096-7192(03)00071-4","article-title":"Gaucher Disease with Parkinsonian Manifestations: Does Glucocerebrosidase Deficiency Contribute to a Vulnerability to Parkinsonism?","volume":"79","author":"Tayebi","year":"2003","journal-title":"Mol. 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