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Mol Biol Cell. 2015 Jan 15;26(2):218-28. doi: 10.1091/mbc.E14-07-1177. Epub 2014 Nov 5.

Polarized sorting of the copper transporter ATP7B in neurons mediated by recognition of a dileucine signal by AP-1.

Author information

1
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
2
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892 bonifacinoj@helix.nih.gov.

Abstract

Neurons are highly polarized cells having distinct somatodendritic and axonal domains. Here we report that polarized sorting of the Cu(2+) transporter ATP7B and the vesicle-SNARE VAMP4 to the somatodendritic domain of rat hippocampal neurons is mediated by recognition of dileucine-based signals in the cytosolic domains of the proteins by the σ1 subunit of the clathrin adaptor AP-1. Under basal Cu(2+) conditions, ATP7B was localized to the trans-Golgi network (TGN) and the plasma membrane of the soma and dendrites but not the axon. Mutation of a dileucine-based signal in ATP7B or overexpression of a dominant-negative σ1 mutant resulted in nonpolarized distribution of ATP7B between the somatodendritic and axonal domains. Furthermore, addition of high Cu(2+) concentrations, previously shown to reduce ATP7B incorporation into AP-1-containing clathrin-coated vesicles, caused loss of TGN localization and somatodendritic polarity of ATP7B. These findings support the notion of AP-1 as an effector of polarized sorting in neurons and suggest that altered polarity of ATP7B in polarized cell types might contribute to abnormal copper metabolism in the MEDNIK syndrome, a neurocutaneous disorder caused by mutations in the σ1A subunit isoform of AP-1.

PMID:
25378584
PMCID:
PMC4294670
DOI:
10.1091/mbc.E14-07-1177
[Indexed for MEDLINE]
Free PMC Article

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