{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:50:38Z","timestamp":1792003838322,"version":"4.4.0"},"reference-count":36,"publisher":"American Chemical Society (ACS)","issue":"40","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100015322","name":"National Cancer Center Japan","doi-asserted-by":"publisher","award":["2023-A-03"],"award-info":[{"award-number":["2023-A-03"]}],"id":[{"id":"10.13039\/100015322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003382","name":"Core Research for Evolutional Science and Technology","doi-asserted-by":"publisher","award":["JPMJCR24B3"],"award-info":[{"award-number":["JPMJCR24B3"]}],"id":[{"id":"10.13039\/501100003382","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["24tk0124003h0002"],"award-info":[{"award-number":["24tk0124003h0002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["24ym0126134h0001"],"award-info":[{"award-number":["24ym0126134h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP22K06171"],"award-info":[{"award-number":["JP22K06171"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP24K01974"],"award-info":[{"award-number":["JP24K01974"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP24K21944"],"award-info":[{"award-number":["JP24K21944"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The PI3K\/AKT signaling pathway is triggered by the recruitment of AKT to cellular membranes. Although AKT is a multidomain serine\/threonine kinase composed of an N-terminal pleckstrin homology (PH) domain and a C-terminal kinase domain (KD), how these domains cooperate to regulate AKT activation on membranes remains unclear at the molecular level. Here, using molecular dynamics simulations of full-length AKT on phosphatidylinositol (3,4,5)-trisphosphate (PIP3)-containing lipid bilayers, we identify four distinct membrane-binding modes that differ in the orientations and membrane contacts of the PH domain and KD. In addition to PIP3 binding to the PH domain, we observed specific PIP3 interactions with basic residues in the KD. In the most stable mode, PIP3 interacts with both the canonical and a secondary binding site in the PH domain, while the KD adopts an orientation in which the activation loop phosphorylation site is exposed to the solvent. The populations of these binding modes depend on the PIP3 concentration in the membrane, leading to changes in the preferred orientation of AKT. Live-cell single-molecule imaging further supports distinct but cooperative roles of the PH domain and KD in membrane recruitment: the PH domain primarily promotes membrane association, whereas the KD enhances recruitment efficiency and stabilizes longer-residence membrane-bound states. These findings suggest that AKT membrane recruitment is governed by cooperative contributions from both the PH domain and the KD, providing molecular insight into how AKT is positioned and stabilized on PIP3-containing membranes.<\/jats:p>","DOI":"10.1021\/jacs.6c13162","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:02:28Z","timestamp":1790704948000},"page":"43423-43432","source":"Crossref","is-referenced-by-count":0,"title":["Cooperative\nMembrane Recognition by Lipid-Sensing\nand Kinase Domains Shapes Membrane-Bound States of AKT"],"prefix":"10.1021","volume":"148","author":[{"given":"Yuki","family":"Nakagaki","sequence":"first","affiliation":[{"name":"Keio University , , , ,","place":["Yokohama, Kanagawa, Japan, 223-8522"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8695-3341","authenticated-orcid":true,"given":"Toshiki","family":"Mori","sequence":"additional","affiliation":[{"name":"Gifu University , , ,","place":["Gifu, Japan, 501-1193"]},{"name":"National Cancer Center Research Institute (NCCRI) , , ,","place":["Tokyo, Japan, 104-0045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi G. N.","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Gifu University , , ,","place":["Gifu, Japan, 501-1193"]},{"name":"National Cancer Center Research Institute (NCCRI) , , ,","place":["Tokyo, Japan, 104-0045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8813-5297","authenticated-orcid":true,"given":"Eiji","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Keio University , , , ,","place":["Yokohama, Kanagawa, Japan, 223-8522"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"2026101414075480400_cit1","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1146\/annurev.biophys.33.110502.133337","article-title":"Membrane-protein\ninteractions in cell signaling and\nmembrane trafficking","volume":"34","author":"Cho","year":"2005","journal-title":"Annu. Rev. Biophys. Biomol.\nStruct."},{"key":"2026101414075480400_cit2","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1096\/fasebj.9.8.7768349","article-title":"The eukaryotic protein kinase superfamily: kinase (catalytic)\ndomain structure and classification","volume":"9","author":"Hanks","year":"1995","journal-title":"Faseb J."},{"key":"2026101414075480400_cit3","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1042\/BST20190013","article-title":"Lipid-dependent\nAkt-ivity: where, when, and how","volume":"47","author":"Siess","year":"2019","journal-title":"Biochem. Soc.\nTrans."},{"issue":"7152","key":"2026101414075480400_cit4","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1038\/nature05933","article-title":"A transforming mutation\nin the pleckstrin homology domain of AKT1 in cancer","volume":"448","author":"Carpten","year":"2007","journal-title":"Nature"},{"key":"2026101414075480400_cit5","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1056\/NEJMoa1104017","article-title":"A mosaic activating mutation in AKT1 associated\nwith the Proteus syndrome","volume":"365","author":"Lindhurst","year":"2011","journal-title":"N. Engl. J. Med."},{"issue":"3","key":"2026101414075480400_cit6","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1016\/j.ymgme.2014.11.018","article-title":"Germline\nactivating AKT3 mutation associated with megalencephaly, polymicrogyria,\nepilepsy and hypoglycemia","volume":"114","author":"Nellist","year":"2015","journal-title":"Mol. Genet. Metab."},{"issue":"8","key":"2026101414075480400_cit7","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1038\/ng.2329","article-title":"De novo\nsomatic mutations in components of the PI3K-AKT3-mTOR\npathway cause hemimegalencephaly","volume":"44","author":"Lee","year":"2012","journal-title":"Nat. Genet."},{"key":"2026101414075480400_cit8","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1126\/science.1096706","article-title":"A family\nwith severe\ninsulin resistance and diabetes due to a mutation in AKT2","volume":"304","author":"George","year":"2004","journal-title":"Science"},{"key":"2026101414075480400_cit9","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1016\/0092-8674(95)90534-0","article-title":"The protein kinase\nencoded by the Akt proto-oncogene is a target of the PDGF-activated\nphosphatidylinositol 3-kinase","volume":"81","author":"Franke","year":"1995","journal-title":"Cell"},{"key":"2026101414075480400_cit10","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.cell.2017.04.001","article-title":"AKT\/PKB Signaling:\nNavigating the Network","volume":"169","author":"Manning","year":"2017","journal-title":"Cell"},{"key":"2026101414075480400_cit11","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1042\/bj3150709","article-title":"Specific\nbinding of the Akt-1 protein kinase to phosphatidylinositol\n3, 4, 5-trisphosphate without subsequent activation","volume":"315","author":"James","year":"1996","journal-title":"Biochem. J."},{"key":"2026101414075480400_cit12","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/sj.onc.1201947","article-title":"Akt activation\nby growth factors is a multiple-step process: the role of the PH domain","volume":"17","author":"Bellacosa","year":"1998","journal-title":"Oncogene"},{"issue":"17","key":"2026101414075480400_cit13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1716109115","article-title":"Conformational sampling of membranes by Akt controls\nits activation and inactivation","volume":"115","author":"Luc\u030cic\u0301","year":"2018","journal-title":"Proc. Natl.\nAcad. Sci. U. S. A."},{"key":"2026101414075480400_cit14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0050095","article-title":"Intramolecular\nand intermolecular interactions of protein kinase B define its activation\nin vivo","volume":"5","author":"Calleja","year":"2007","journal-title":"PLoS Biol."},{"issue":"33","key":"2026101414075480400_cit15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2101496118","article-title":"Structure\nof autoinhibited Akt1 reveals mechanism of\nPIP3-mediated activation","volume":"118","author":"Truebestein","year":"2021","journal-title":"Proc. Natl.\nAcad. Sci. U. S. A."},{"key":"2026101414075480400_cit16","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.molcel.2016.12.028","article-title":"PI (3, 4,\n5) P3 Engagement Restricts Akt Activity to Cellular Membranes","volume":"65","author":"Ebner","year":"2017","journal-title":"Mol. Cell"},{"key":"2026101414075480400_cit17","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/S0960-9822(06)00122-9","article-title":"Characterization of\na 3-phosphoinositide-dependent\nprotein kinase which phosphorylates and activates protein kinase B\u03b1","volume":"7","author":"Alessi","year":"1997","journal-title":"Curr. Biol."},{"key":"2026101414075480400_cit18","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.1126\/science.1106148","article-title":"Phosphorylation\nand Regulation of Akt\/PKB by the Rictor-mTOR complex","volume":"307","author":"Sarbassov","year":"2005","journal-title":"Science"},{"key":"2026101414075480400_cit19","doi-asserted-by":"publisher","first-page":"7482","DOI":"10.1038\/sj.onc.1209088","article-title":"The Akt\/PKB\npathway: molecular target for cancer drug discovery","volume":"24","author":"Cheng","year":"2005","journal-title":"Oncogene"},{"key":"2026101414075480400_cit20","doi-asserted-by":"publisher","first-page":"5511","DOI":"10.1038\/onc.2008.246","article-title":"Drug discovery approaches targeting the PI3K\/Akt pathway\nin cancer","volume":"27","author":"Garcia-Echeverria","year":"2008","journal-title":"Oncogene"},{"issue":"1","key":"2026101414075480400_cit21","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1038\/s41392-021-00828-5","article-title":"Targeting\nPI3K\/Akt signal transduction\nfor cancer therapy","volume":"6","author":"He","year":"2021","journal-title":"Signal Transduction Targeted\nTher."},{"key":"2026101414075480400_cit22","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1042\/bj20031229","article-title":"Binding\nof phosphatidylinositol 3,4,5-trisphosphate\nto the pleckstrin homology domain of protein kinase B induces a conformational\nchange","volume":"375","author":"Milburn","year":"2003","journal-title":"Biochem. J."},{"key":"2026101414075480400_cit23","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1016\/j.str.2016.06.002","article-title":"Interactions\nof Pleckstrin Homology Domains with Membranes: Adding Back the Bilayer\nvia High-Throughput Molecular Dynamics","volume":"24","author":"Yamamoto","year":"2016","journal-title":"Structure"},{"issue":"27","key":"2026101414075480400_cit24","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abn6992","article-title":"Systematic\nsimulation of the interactions of pleckstrin homology domains with\nmembranes","volume":"8","author":"Le Huray","year":"2022","journal-title":"Sci. Adv."},{"key":"2026101414075480400_cit25","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.str.2024.10.020","article-title":"Two cooperative\nlipid binding sites within the pleckstrin homology domain are necessary\nfor AKT binding and stabilization to the plasma membrane","volume":"33","author":"Soteriou","year":"2025","journal-title":"Structure"},{"key":"2026101414075480400_cit26","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction\nwith AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"2026101414075480400_cit27","doi-asserted-by":"publisher","first-page":"D439","DOI":"10.1093\/nar\/gkab1061","article-title":"AlphaFold Protein Structure Database: massively expanding\nthe structural coverage of protein-sequence space with high-accuracy\nmodels","volume":"50","author":"Varadi","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"2026101414075480400_cit28","doi-asserted-by":"publisher","first-page":"4176","DOI":"10.1021\/ct400008p","article-title":"Toward\nOptimized Potential Functions\nfor Protein\u2013Protein Interactions in Aqueous Solutions: Osmotic\nSecond Virial Coefficient Calculations Using the MARTINI Coarse-Grained\nForce Field","volume":"9","author":"Stark","year":"2013","journal-title":"J. Chem. Theory Comput."},{"key":"2026101414075480400_cit29","doi-asserted-by":"publisher","first-page":"2033","DOI":"10.1021\/acs.jctc.1c01042","article-title":"Improving\nMartini 3 for Disordered and Multidomain Proteins","volume":"18","author":"Thomasen","year":"2022","journal-title":"J. Chem. Theory Comput."},{"issue":"1","key":"2026101414075480400_cit30","doi-asserted-by":"publisher","first-page":"6645","DOI":"10.1038\/s41467-024-50647-9","article-title":"Rescaling protein-protein interactions\nimproves Martini 3 for flexible proteins in solution","volume":"15","author":"Thomasen","year":"2024","journal-title":"Nat. Commun."},{"issue":"1","key":"2026101414075480400_cit31","doi-asserted-by":"publisher","first-page":"18245","DOI":"10.1038\/srep18245","article-title":"Anomalous\nDynamics of a Lipid Recognition Protein on a Membrane Surface","volume":"5","author":"Yamamoto","year":"2015","journal-title":"Sci. Rep."},{"issue":"8","key":"2026101414075480400_cit32","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aay5736","article-title":"Multiple lipid binding sites determine\nthe affinity of PH domains for phosphoinositide-containing membranes","volume":"6","author":"Yamamoto","year":"2020","journal-title":"Sci. Adv."},{"key":"2026101414075480400_cit33","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1038\/s41580-022-00490-x","article-title":"Phosphoinositides as membrane organizers","volume":"23","author":"Posor","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2026101414075480400_cit34","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1038\/s41592-023-02085-6","article-title":"StayGold\nvariants for molecular fusion and\nmembrane-targeting applications","volume":"21","author":"Ando","year":"2024","journal-title":"Nat. Methods"},{"key":"2026101414075480400_cit35","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1158\/2159-8290.CD-16-0160","article-title":"Systematic functional\ninterrogation of rare cancer variants identifies\noncogenic alleles","volume":"6","author":"Kim","year":"2016","journal-title":"Cancer Discovery"},{"issue":"1","key":"2026101414075480400_cit36","doi-asserted-by":"publisher","first-page":"2111","DOI":"10.1038\/s41467-022-29638-1","article-title":"AKT mutant allele-specific\nactivation dictates pharmacologic sensitivities","volume":"13","author":"Shrestha Bhattarai","year":"2022","journal-title":"Nat. Commun."}],"container-title":["Journal of the American\nChemical Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jacs.6c13162","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/148\/40\/43423\/68702031\/jacs.6c13162.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/148\/40\/43423\/68702031\/jacs.6c13162.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:30:21Z","timestamp":1792002621000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jacsat\/article\/148\/40\/43423\/5441790\/Cooperative-Membrane-Recognition-by-Lipid-Sensing"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":36,"journal-issue":{"issue":"40","published-online":{"date-parts":[[2026,9,29]]},"published-print":{"date-parts":[[2026,10,14]]}},"URL":"https:\/\/doi.org\/10.1021\/jacs.6c13162","relation":{},"ISSN":["0002-7863","1520-5126"],"issn-type":[{"value":"0002-7863","type":"print"},{"value":"1520-5126","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]}}}