{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T06:39:32Z","timestamp":1790923172107,"version":"4.1.0"},"reference-count":46,"publisher":"American Physiological Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2009,2]]},"abstract":"<jats:p> ATP7B is a copper-transporting P-type ATPase present predominantly in liver. In basal copper, hepatic ATP7B is in a post-trans-Golgi network (TGN) compartment where it loads cytoplasmic Cu(I) onto newly synthesized ceruloplasmin. When copper levels rise, the protein redistributes via unique vesicles to the apical periphery where it exports intracellular Cu(I) into bile. We want to understand the mechanisms regulating the copper-sensitive trafficking of ATP7B. Earlier, our laboratory reported the presence of apical targeting\/TGN retention information within residues 1\u201363 of human ATP7B; deletion of these residues resulted in a mutant protein that was not efficiently retained in the post-TGN in low copper and constitutively trafficked to the basolateral membrane of polarized, hepatic WIF-B cells with and without copper ( 13 ). In this study, we used mutagenesis and adenovirus infection of WIF-B cells followed by confocal immunofluorescence microscopy analysis to identify the precise retention\/targeting sequences in the context of full-length ATP7B. We also analyzed the expression of selected mutants in livers of copper-deficient and -loaded mice. Our combined results clearly demonstrate that nine amino acids, F<jats:sub>37<\/jats:sub>AFDNVGYE<jats:sub>45<\/jats:sub>, comprise an essential apical targeting determinant for ATP7B in elevated copper and participate in the TGN retention of the protein under low-copper conditions. The signal is novel, does not require phosphorylation, and is highly conserved in \u223c24 species of ATP7B. Furthermore, N41S, which is part of the signal we identified, is the first and only Wilson disease-causing missense mutation in residues 1\u201363 of ATP7B. Expression of N41S-ATP7B in WIF-B cells severely disabled the targeting and retention of the protein. We present a working model of how this physiologically relevant signal might work. <\/jats:p>","DOI":"10.1152\/ajpgi.90489.2008","type":"journal-article","created":{"date-parts":[[2008,11,26]],"date-time":"2008-11-26T04:33:49Z","timestamp":1227674029000},"page":"G433-G444","source":"Crossref","is-referenced-by-count":79,"title":["Apical targeting and Golgi retention signals reside within a 9-amino acid sequence in the copper-ATPase, ATP7B"],"prefix":"10.1152","volume":"296","author":[{"given":"Lelita","family":"Braiterman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"Nyasae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo","family":"Bustos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana","family":"Lutsenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Hubbard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0504472103"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1021\/bi8004736"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(93)90734-T"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.105.3.1241"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.01-07-0376"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1080\/07315724.2007.10719643"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.115.5.1397"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20061055"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2005.10.054"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1016\/j.tvjl.2007.04.012"},{"key":"R11","unstructured":"Deguti MM, Genschel J, Cancado EL, Barbosa ER, Bochow B, Mucenic M, Porta G, Lochs H, Carrilho FJ, Schmidt HH. 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