{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T09:16:38Z","timestamp":1788167798038,"version":"build-2803163510"},"reference-count":53,"publisher":"American Chemical Society (ACS)","issue":"16","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/na","name":"Anusandhan National Research Foundation","doi-asserted-by":"publisher","award":["ANRF\/ECRG\/2024\/003501\/LS"],"award-info":[{"award-number":["ANRF\/ECRG\/2024\/003501\/LS"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The failure of \u03b3-secretase inhibitors in clinical trials of Alzheimer\u2019s disease (AD) has shifted the focus toward more selective targets, specifically SPPL2a (signal peptide-peptidase-like 2a), which is emerging as a critical therapeutic target in AD because of its role in processing TMEM106B. While recent cryo-EM structures have provided essential static snapshots, the dynamic mechanisms governing substrate entry and inhibitor recognition remain unresolved. Here, we present the first microsecond-time scale, all-atom molecular dynamics characterization of human SPPL2a in its apo and inhibitor-bound states, alongside a comparative analysis of the \u03b3-secretase catalytic subunit, PS1. Our simulations reveal that SPPL2a is highly dynamic and undergoes an inhibitor-induced disorder-to-order transition in the TM6a region, where the helicity increases from 10% to 77%. We characterized the lateral gate dynamics of TM2, revealing that inhibitor binding fundamentally remodels the interhelical contact network and quenches conformational sampling. Moreover, we identified a unique inhibitor-stabilized lipid hotspot at Trp189 and demonstrated that SPPL2a utilizes a distributed polar network for binding energy, in contrast to the concentrated aspartate-driven affinity of PS1. These findings provide a quantitative atomistic blueprint of SPPL2a dynamics, offering a structural basis that can be exploited for the design of selectivity-guided therapeutics to bypass the clinical failures associated with nonspecific intramembrane protease inhibition.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c01556","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T06:04:09Z","timestamp":1784527449000},"page":"10088-10102","source":"Crossref","is-referenced-by-count":0,"title":["Unlocking the Dynamics\nof Human SPPL2a: First Atomistic\nCharacterization of an Alzheimer\u2019s-Linked Intramembrane Protease"],"prefix":"10.1021","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2370-2538","authenticated-orcid":true,"given":"Sagnika","family":"Dutta","sequence":"first","affiliation":[{"name":"Manipal Academy of Higher Education , , Manipal, ,","place":["Udupi, India, 576104"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahender Kumar","family":"Singh","sequence":"additional","affiliation":[{"name":"National Brain Research Centre , , , ,","place":["Gurgaon, Haryana, India, 122052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9726-8454","authenticated-orcid":true,"given":"Budheswar","family":"Dehury","sequence":"additional","affiliation":[{"name":"Manipal Academy of Higher Education , , Manipal, ,","place":["Udupi, India, 576104"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"issue":"7245","key":"2026083104293743100_cit1","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1038\/nature08146","article-title":"How Intramembrane Proteases Bury\nHydrolytic Reactions in the Membrane","volume":"459","author":"Erez","year":"2009","journal-title":"Nature"},{"issue":"1","key":"2026083104293743100_cit2","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1038\/s42003-023-04654-z","article-title":"In Vivo Characterization\nof the Bacterial Intramembrane-Cleaving Protease RseP Using the Heme\nBinding Tag-Based Assay iCliPSpy","volume":"6","author":"Kupke","year":"2023","journal-title":"Commun. Biol."},{"issue":"1","key":"2026083104293743100_cit3","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/S1097-2765(00)80006-4","article-title":"Complementation\nCloning of S2P, a Gene Encoding a Putative Metalloprotease Required\nfor Intramembrane Cleavage of SREBPs","volume":"1","author":"Rawson","year":"1997","journal-title":"Mol. Cell"},{"key":"2026083104293743100_cit4","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.adt2272","article-title":"Insights into the Intramembrane\nProtease SPPL2b and Its Substrates: Functions and Disease Implications","volume":"18","author":"Badman","year":"2025","journal-title":"Sci. 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Biol."},{"issue":"17","key":"2026083104293743100_cit49","doi-asserted-by":"publisher","first-page":"3565","DOI":"10.1021\/bi300303g","article-title":"Effects\nof Membrane Lipids on the Activity and Processivity of Purified \u03b3-Secretase","volume":"51","author":"Holmes","year":"2012","journal-title":"Biochemistry"},{"issue":"4","key":"2026083104293743100_cit50","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1002\/pro.2585","article-title":"Influence of Hydrophobic\nMismatch on the Catalytic Activity of Rhomboid Protease","volume":"24","author":"Foo","year":"2015","journal-title":"Protein Sci."},{"issue":"38","key":"2026083104293743100_cit51","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abq8303","article-title":"Rhomboid-Catalyzed\nIntramembrane Proteolysis Requires Hydrophobic Matching with the Surrounding\nLipid Bilayer","volume":"8","author":"Engberg","year":"2022","journal-title":"Sci. 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B"},{"issue":"52","key":"2026083104293743100_cit53","doi-asserted-by":"publisher","first-page":"31215","DOI":"10.1039\/D0RA04683C","article-title":"Side-by-Side Comparison\nof Notch- and C83 Binding to \u03b3-Secretase\nin a Complete Membrane Model at Physiological Temperature","volume":"10","author":"Dehury","year":"2020","journal-title":"RSC Adv."}],"container-title":["Journal of Chemical Information\nand Modeling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jcim.6c01556","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/66\/16\/10088\/66035392\/acs.jcim.6c01556.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/66\/16\/10088\/66035392\/acs.jcim.6c01556.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T08:29:46Z","timestamp":1788164986000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article\/66\/16\/10088\/5215848\/Unlocking-the-Dynamics-of-Human-SPPL2a-First"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,20]]},"references-count":53,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,7,20]]},"published-print":{"date-parts":[[2026,8,24]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jcim.6c01556","relation":{},"ISSN":["1549-9596","1549-960X"],"issn-type":[{"value":"1549-9596","type":"print"},{"value":"1549-960X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,20]]}}}