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J Biol Chem. 2018 Oct 5;293(40):15678-15690. doi: 10.1074/jbc.RA118.003080. Epub 2018 Aug 22.

Phosphoserine acidic cluster motifs bind distinct basic regions on the μ subunits of clathrin adaptor protein complexes.

Author information

1
From the Department of Medicine, University of California San Diego, La Jolla, California 92093, rks003@ucsd.edu.
2
From the Department of Medicine, University of California San Diego, La Jolla, California 92093.
3
the Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06510.
4
the Department of Chemistry and Biochemistry, University of Massachusetts, Dartmouth, Massachusetts 02747.
5
the Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, California 92037, and.
6
From the Department of Medicine, University of California San Diego, La Jolla, California 92093, jguatelli@ucsd.edu.
7
the Veterans Affairs San Diego Healthcare System, San Diego, California 92161.

Abstract

Protein trafficking in the endosomal system involves the recognition of specific signals within the cytoplasmic domains (CDs) of transmembrane proteins by clathrin adaptors. One such signal is the phosphoserine acidic cluster (PSAC), the prototype of which is in the endoprotease furin. How PSACs are recognized by clathrin adaptors has been controversial. We reported previously that HIV-1 Vpu, which modulates cellular immunoreceptors, contains a PSAC that binds to the μ subunits of clathrin adaptor protein (AP) complexes. Here, we show that the CD of furin binds the μ subunits of AP-1 and AP-2 in a phosphorylation-dependent manner. Moreover, we identify a potential PSAC in a cytoplasmic loop of the cellular transmembrane Serinc3, an inhibitor of the infectivity of retroviruses. The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the μ subunits in vitro The sites of these serines vary among mammals in a manner suggesting host-pathogen conflict, yet the Serinc3 PSAC seems dispensable for anti-HIV activity and for counteraction by HIV-1 Nef. The CDs of Vpu and furin and the PSAC-containing loop of Serinc3 each bind the μ subunit of AP-2 (μ2) with similar affinities, but they appear to utilize different basic regions on μ2. The Serinc3 loop requires a region previously reported to bind the acidic plasma membrane lipid phosphatidylinositol 4,5-bisphosphate. These data suggest that the PSACs within different proteins recognize different basic regions on the μ surface, providing the potential to inhibit the activity of viral proteins without necessarily affecting cellular protein trafficking.

KEYWORDS:

HIV-1 Vpu; Serinc3; acidic cluster; adaptor protein; clathrin; furin; host-pathogen interaction; human immunodeficiency virus (HIV); kinetics; medium subunit; membrane trafficking; phosphorylation; phosphoserine; protein chemistry; protein complex

PMID:
30135209
PMCID:
PMC6177606
[Available on 2019-10-05]
DOI:
10.1074/jbc.RA118.003080
[Indexed for MEDLINE]

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