{"id":13394,"date":"2023-09-10T13:03:00","date_gmt":"2023-09-10T13:03:00","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=13394"},"modified":"2024-01-11T13:03:17","modified_gmt":"2024-01-11T13:03:17","slug":"2023-pi-35p2-mediated-oligomerization-of-the-endosomal-sodium-proton-exchanger-nhe9","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2023-pi-35p2-mediated-oligomerization-of-the-endosomal-sodium-proton-exchanger-nhe9\/","title":{"rendered":"2023 &#8211; PI-(3,5)P2-mediated oligomerization of the endosomal sodium\/proton exchanger NHE9"},"content":{"rendered":"<p>Na<sup>+<\/sup>\/H<sup>+<\/sup>\u00a0exchangers (NHE) are found in all cells to regulate intracellular pH, sodium levels and cell volume. The NHE isoform 9 (SLC9A9) fine-tunes endosomal pH, and its activity is linked to glioblastoma, epilepsy, autism spectrum and attention-deficit-hyperactivity disorders. Here, we report cryo-EM structures of\u00a0<em>horse<\/em>\u00a0NHE9 and a cysteine-variant at 3.6 and 3.1 \u00c5 resolution, respectively. We show how lysine residues, from a previously unresolved TM2-TM3 \u03b2-hairpin loop domain, are positioned above the dimerization interface and interact with the endosomal-specific PI-(3,5)P<sub>2<\/sub>\u00a0lipid, together with residues located on dimer domain helices. Thermal-shift assays, solid-state membrane (SSM) electrophysiology and MD simulations, corroborates that NHE9 can specifically bind PI-(3,5)P<sub>2<\/sub>, and that its addition stabilizes the homodimer and enhances NHE9 activity. We have further determined the cryo-EM structure of\u00a0<em>E. coli<\/em>\u00a0NhaA, confirming the expected coordination of cardiolipin at the dimerization interface, solidifying the concept that Na<sup>+<\/sup>\/H<sup>+<\/sup>\u00a0exchanger dimerization and transporter activity can be regulated by specific lipids. Taken together, we propose that the activity of NHE9 is regulated by the PI-(3,5)P<sub>2<\/sub>\u00a0lipid upon reaching endosomes, which we refer to as an lipid-activation-upon-arrival model.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[36],"resource_type":[75],"application_areas":[53,108],"therapeutic_areas":[143],"target_categories":[60],"target_families":[343],"targets":[],"resource_keyword":[],"class_list":["post-13394","resource_library","type-resource_library","status-publish","hentry","products_tags-surfe2r-n1","resource_type-publication","application_areas-assay-development-and-validation","application_areas-transporters","therapeutic_areas-assay-development-and-validation","target_categories-transporters","target_families-exchanger"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/13394","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/media?parent=13394"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=13394"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=13394"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=13394"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=13394"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=13394"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=13394"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=13394"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=13394"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}