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| The EMBO Journal
(2001) 20, 2191–2201, doi:10.1093/emboj/20.9.2191 |
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| PACS-1 binding to adaptors is required for acidic cluster motif-mediated protein traffic |
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| Colin M. Crump1, 4, Yang Xiang2, 4, Laurel Thomas1, Feng Gu1, Carol Austin3, Sharon A. Tooze3 and Gary Thomas1 |
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1 Vollum Institute, L-474, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97201-3098, USA 2 HHMI, Beckman Center B161, Stanford University, Palo Alto, CA 94304, USA 3 Imperial Cancer Research Fund, PO Box 123, Lincoln Inn Fields, London WC2A 3PX, UK 4 C.M.Crump and Y.Xiang contributed equally to this work To whom correspondence should be addressed Gary Thomas, thomasg@ohsu.edu Received 14 November 2000; Revised 26 February 2001; Accepted 13 March 2001. |
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| Abstract |
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| PACS-1 is a cytosolic protein involved in controlling the correct subcellular localization of integral membrane proteins that contain acidic cluster sorting motifs, such as furin and human immunodeficiency virus type 1 (HIV-1) Nef. We have now investigated the interaction of PACS-1 with heterotetrameric adaptor complexes. PACS-1 associates with both AP-1 and AP-3, but not AP-2, and forms a ternary complex between furin and AP-1. A short sequence within PACS-1 that is essential for binding to AP-1 has been identified. Mutation of this motif yielded a dominant-negative PACS-1 molecule that can still bind to acidic cluster motifs on cargo proteins but not to adaptor complexes. Expression of dominant-negative PACS-1 causes a mislocalization of both furin and mannose 6-phosphate receptor from the trans-Golgi network, but has no effect on the localization of proteins that do not contain acidic cluster sorting motifs. Furthermore, expression of dominant-negative PACS-1 inhibits the ability of HIV-1 Nef to downregulate MHC-I. These studies demonstrate the requirement for PACS-1 interactions with adaptor proteins in multiple processes, including secretory granule biogenesis and HIV-1 pathogenesis. |
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| Keywords: adaptors, furin, Nef, PACS-1, secretory granule |
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