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Vol. 11, Issue 4, 1257-1273, April 2000
*Vollum Institute and The mammalian proprotein convertases (PCs) are a family of
secretory pathway enzymes that catalyze the endoproteolytic maturation of peptide hormones and many bioactive proteins. Two PCs, furin and
PC6B, are broadly expressed and share very similar cleavage site
specificities, suggesting that they may be functionally redundant. However, germline knockout studies show that they are not. Here we
report the distinct subcellular localization of PC6B and identify the
sorting information within its cytoplasmic domain (cd). We show that in
neuroendocrine cells, PC6B is localized to a paranuclear, brefeldin
A-dispersible, BaCl2-responsive post-Golgi network (TGN) compartment distinct from furin and TGN38. The 88-amino acid PC6B-cd contains sorting information sufficient to direct reporter proteins to
the same compartment as full-length PC6B. Mutational analysis indicates
that endocytosis is predominantly directed by a canonical tyrosine-based motif (Tyr1802GluLysLeu). Truncation and
sufficiency studies reveal that two clusters of acidic amino acids
(ACs) within the PC6B-cd contain differential sorting information. The
membrane-proximal AC (AC1) directs TGN localization and interacts with
the TGN sorting protein PACS-1. The membrane-distal AC (AC2) promotes a
localization characteristic of the full-length PC6B-cd. Our results
demonstrate that AC motifs can target proteins to distinct
TGN/endosomal compartments and indicate that the AC-mediated
localization of PC6B and furin contribute to their distinct roles in vivo.
Department of Cell and
Developmental Biology, Oregon Health Sciences University, Portland,
Oregon 97201
Corresponding author. E-mail address:
thomasg{at}ohsu.edu.
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