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They are generally classified as type-3 copper proteins, with binuclear copper active sites. Although there is experimental evidence for a copper cofactor in TYR, delivered via the copper transporter, ATP7A, the presence of copper in TYRP1 and TYRP2 has not been demonstrated. Here, we report that the expression and function of TYRP1 requires zinc, mediated by ZNT5\u2013ZNT6 heterodimers (ZNT5\u20136) or ZNT7\u2013ZNT7 homodimers (ZNT7). Loss of ZNT5\u20136 and ZNT7 function results in hypopigmentation in medaka fish and human melanoma cells, and is accompanied by immature melanosomes and reduced melanin content, as observed in TYRP1 dysfunction. The requirement of ZNT5\u20136 and ZNT7 for TYRP1 expression is conserved in human, mouse, and chicken orthologs. Our results provide novel insights into the pigmentation process and address questions regarding metalation in tyrosinase protein family.<\/jats:p>","DOI":"10.1038\/s42003-023-04640-5","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T06:03:29Z","timestamp":1681797809000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Pigmentation and TYRP1 expression are mediated by zinc through the early secretory pathway-resident ZNT proteins"],"prefix":"10.1038","volume":"6","author":[{"given":"Takumi","family":"Wagatsuma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eisuke","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miku","family":"Shiotsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Sogo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukina","family":"Nishito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideya","family":"Ando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisashi","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Petris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3936-7371","authenticated-orcid":false,"given":"Masato","family":"Kinoshita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9757-063X","authenticated-orcid":false,"given":"Taiho","family":"Kambe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,4,18]]},"reference":[{"key":"4640_CR1","doi-asserted-by":"publisher","first-page":"a017046","DOI":"10.1101\/cshperspect.a017046","volume":"4","author":"Y Yamaguchi","year":"2014","unstructured":"Yamaguchi, Y. & Hearing, V. 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