PACS‐1 binding to adaptors is required for acidic cluster motif‐mediated protein traffic

Colin M. Crump, Yang Xiang, Laurel Thomas, Feng Gu, Carol Austin, Sharon A. Tooze, Gary Thomas

Author Affiliations

  1. Colin M. Crump1,4,
  2. Yang Xiang2,4,
  3. Laurel Thomas1,
  4. Feng Gu1,
  5. Carol Austin3,
  6. Sharon A. Tooze3 and
  7. Gary Thomas*,1
  1. 1 Vollum Institute, L‐474, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR, 97201‐3098, USA
  2. 2 HHMI, Beckman Center B161, Stanford University, Palo Alto, CA, 94304, USA
  3. 3 Imperial Cancer Research Fund, PO Box 123, Lincoln Inn Fields, London, WC2A 3PX, UK
  4. 4 C.M.Crump and Y.Xiang contributed equally to this work
  1. *Corresponding author. E-mail: thomasg{at}
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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.

  • Received November 14, 2000.
  • Revision received February 26, 2001.
  • Accepted March 13, 2001.
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