{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:31:33Z","timestamp":1789191093848,"version":"build-2803163510"},"reference-count":55,"publisher":"National Academy of Sciences","issue":"22","license":[{"start":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T00:00:00Z","timestamp":1748390400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM039478"],"award-info":[{"award-number":["R01GM039478"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM116961"],"award-info":[{"award-number":["R01GM116961"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,6,3]]},"abstract":"<jats:p>Spleen tyrosine kinase (Syk) mediates early signaling events in immunity by coupling membrane receptors to immune responses. Syk comprises a tandem SH2 (tSH2) regulatory module\u2014two SH2 domains connected by a structured linker\u2014and a kinase domain. The association of tSH2 with a doubly tyrosine-phosphorylated motif (dpITAM) on membrane immunoreceptors is central to controlling Syk\u2019s signaling activity. tSH2-dpITAM association is regulated by Y131-phosphorylation on linker A, distant from the Syk\u2013immunoreceptor binding sites. A unique thermodynamic signature was reported to control this protein\u2013protein interaction by phosphorylation, yet the molecular mechanism for the phosphorylation effect is unknown. Molecular dynamics (MD) simulation affords the detail needed to fill this knowledge deficiency. Long MD simulations revealed a highly correlated interdomain electrostatic network (distance correlation coefficients &gt; 0.75) that is lost upon Y131-phosphorylation. Some of the strongly correlated interdomain pairs carry the same charge or are separated by distances greater than a salt-bridge pair. The strong interdomain connectivity accounts for the single, narrow free energy basin in the domain-structure conformational landscape for unphosphorylated tSH2. Linker phosphorylation disrupts this network and yields a broader free energy landscape with multiple networks formed by the same group of residues adopting alternative interdomain conformations. A salt dependence of NMR rotational tumbling times substantiates the electrostatic nature of tSH2 domain\u2013domain coupling. Syk tandem SH2 is thus a sensor whose conformational plasticity is sensitive to Y131 phosphorylation. This phospho-sensing response provides the basis for an entropically driven regulatory mechanism that is so-far unique to Syk\u2013immunoreceptor protein\u2013protein association.<\/jats:p>","DOI":"10.1073\/pnas.2421663122","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T11:06:42Z","timestamp":1748430402000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["An electrostatic network with strong connectivity is a phospho-sensor for regulating affinity of Syk\u2013receptor association"],"prefix":"10.1073","volume":"122","author":[{"given":"Duy P.","family":"Hua","sequence":"first","affiliation":[{"name":"Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University","place":["West Lafayette"]},{"name":"Department of Biological Sciences, Markey Center for Structural Biology, and Purdue Center for Cancer Research, Purdue University","place":["West Lafayette"]},{"name":"The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob J.","family":"Kinnun","sequence":"additional","affiliation":[{"name":"Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University","place":["West Lafayette"]},{"name":"Department of Biological Sciences, Markey Center for Structural Biology, and Purdue Center for Cancer Research, Purdue University","place":["West Lafayette"]},{"name":"Department of Chemistry, University of Tennessee","place":["Knoxville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5233-899X","authenticated-orcid":false,"given":"Carol Beth","family":"Post","sequence":"additional","affiliation":[{"name":"Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University","place":["West Lafayette"]},{"name":"Department of Biological Sciences, Markey Center for Structural Biology, and Purdue Center for Cancer Research, Purdue University","place":["West Lafayette"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,5,28]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/338383b0"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.155.7.3281"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M909044199"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(02)00739-6"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2009.03.004"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2765"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.008045"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201041326"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0708583105"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1039\/C5CP05417F"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2012.11.007"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01637-12"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4199"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr000225s"},{"key":"e_1_3_4_15_2","first-page":"957","article-title":"Structural insights into protein regulation by phosphorylation and substrate recognition of protein kinases\/phosphatases","volume":"11","author":"Seok S.-H.","year":"2021","unstructured":"S.-H. Seok, Structural insights into protein regulation by phosphorylation and substrate recognition of protein kinases\/phosphatases. eLife 11, 957 (2021).","journal-title":"eLife"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2009.02.007"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13999"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1008242107"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0703151104"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2013.09.014"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3489"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1998.1964"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar5002318"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1021\/ct300565f"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1119174109"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1810324115"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.5b00796"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.8b00147"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(98)77671-4"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.10.4691"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-2214-7_23"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.7b00305"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-440X(00)00065-8"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.14197"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1110\/ps.037457.108"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1984.tb02223.x"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1008305808620"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.16.10377"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.0020032"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmre.2000.2170"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.22927"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(86)90015-X"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.340110305"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1996.0562"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi026465e"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.4825247"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.1839571"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1021\/ct500200n"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5560070314"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2012.10.003"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1385\/1-59259-890-0:571"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmre.2000.2022"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00197809"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu830"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00155a020"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2421663122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T11:07:17Z","timestamp":1748430437000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2421663122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,28]]},"references-count":55,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2025,6,3]]}},"alternative-id":["10.1073\/pnas.2421663122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2421663122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,28]]},"assertion":[{"value":"2024-10-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2421663122"}}