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

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

Research output: Contribution to journalArticlepeer-review

149 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2191-2201
Number of pages11
JournalEMBO Journal
Volume20
Issue number9
DOIs
StatePublished - May 1 2001
Externally publishedYes

Keywords

  • Adaptors
  • Furin
  • Nef
  • PACS-1
  • Secretory granule

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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