{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T01:45:20Z","timestamp":1776217520732,"version":"3.50.1"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,12,7]],"date-time":"2020-12-07T00:00:00Z","timestamp":1607299200000},"content-version":"vor","delay-in-days":1064,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"},{"start":{"date-parts":[[2019,1,8]],"date-time":"2019-01-08T00:00:00Z","timestamp":1546905600000},"content-version":"am","delay-in-days":365,"URL":"http:\/\/rsc.li\/journals-terms-of-use"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["10SDG4120011"],"award-info":[{"award-number":["10SDG4120011"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["10SDG4120011"],"award-info":[{"award-number":["10SDG4120011"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["rsc.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,2,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is activated by ATP binding at the interface of two cytoplasmic nucleotide binding domains (NBDs) and phosphorylation of the regulatory (R) domain by protein kinase A (PKA). The human CFTR has two functionally active thiol groups for gating regulation by chemical modification. Although modification of C832 in the R domain with N-ethylmaleimide promotes channel opening, glutathionylation of C1344 in NBD2 inhibits channel opening. Our recent studies demonstrated that the N-ethylmaleimide-induced potentiation involves a high-affinity inhibitory Fe3+ site at the interface between the R domain and intracellular loop 3 (ICL3). However, it is unknown whether the glutathionylation-evoked inhibition implies another stimulatory metal site. Here, Fe3+-insensitive mutations at the R\u2013ICL3 interface were employed to further examine whether Zn2+ potentiated the activity of the human CFTR channel by targeting C1344 once the interfacial Fe3+ bridge was disrupted. The results showed that internal nanomolar Zn2+ increased its activity by about two- to threefold at a low level of protein kinase A, and the increase was reversed by EDTA or DTT or reduced glutathione but suppressed by a high level of protein kinase A, N-ethylmaleimide modification or a C1344A mutation. It is interesting that this Zn2+-triggered potentiation is not found in the wild type human CFTR to which endogenous Fe3+ is bound. Thus, the high-affinity binding of Zn2+ to C1344 in NBD2 may stimulate human CFTR activity in a phosphorylation-dependent manner, but the primary binding of Fe3+ to the ICL3\u2013R interface may prohibit this stimulation.<\/jats:p>","DOI":"10.1039\/c7mt00315c","type":"journal-article","created":{"date-parts":[[2018,1,8]],"date-time":"2018-01-08T07:35:09Z","timestamp":1515396909000},"page":"240-247","update-policy":"https:\/\/doi.org\/10.1039\/rsc_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Removal of the Fe(\n                    <scp>iii<\/scp>\n                    ) site promotes activation of the human cystic fibrosis transmembrane conductance regulator by high-affinity Zn(\n                    <scp>ii<\/scp>\n                    ) binding"],"prefix":"10.1093","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5581-6926","authenticated-orcid":false,"given":"Guangyu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics and Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham , Birmingham, AL 39254,","place":["USA"]},{"name":"Department of Pharmacology, University of Nevada School of Medicine , Reno, NV 89557,","place":["USA"]},{"name":"Department of Drug Research and Development, Institute of Biophysical Medico-chemistry , Reno, NV 89523,","place":["USA"]},{"name":"Department of Physiology and Membrane Biology, University of California School of Medicine , Davis, CA 95616,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2018,1,8]]},"reference":[{"key":"2026041420234543400_cit1","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1126\/science.2475911","article-title":"Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA","volume":"245","author":"Riordan","year":"1989","journal-title":"Science"},{"key":"2026041420234543400_cit2","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.cell.2017.06.041","article-title":"Conformational Changes of CFTR upon Phosphorylation and ATP Binding","volume":"170","author":"Zhang","year":"2017","journal-title":"Cell"},{"key":"2026041420234543400_cit3","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.cell.2017.02.024","article-title":"Molecular Structure of the human CFTR ion channel","volume":"169","author":"Liu","year":"2017","journal-title":"Cell"},{"key":"2026041420234543400_cit4","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1038\/nature03313","article-title":"CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains","volume":"433","author":"Vergani","year":"2005","journal-title":"Nature"},{"key":"2026041420234543400_cit5","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nature04712","article-title":"The ABC protein turned chloride channel whose failure causes cystic fibrosis","volume":"440","author":"Gadsby","year":"2006","journal-title":"Nature"},{"key":"2026041420234543400_cit6","doi-asserted-by":"crossref","first-page":"4728","DOI":"10.1038\/sj.emboj.7601373","article-title":"In vivo phosphorylation of CFTR promotes formation of a nucleotide-binding domain heterodimer","volume":"25","author":"Mense","year":"2006","journal-title":"EMBO J."},{"key":"2026041420234543400_cit7","doi-asserted-by":"crossref","first-page":"5657","DOI":"10.1073\/pnas.100588797","article-title":"A functional R domain from cystic fibrosis transmembrane conductance regulator is predominantly unstructured in solution","volume":"97","author":"Ostedgaard","year":"2000","journal-title":"Proc. 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