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PMID:20351172

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Citation

Wu-Baer, F, Ludwig, T and Baer, R (2010) The UBXN1 protein associates with autoubiquitinated forms of the BRCA1 tumor suppressor and inhibits its enzymatic function. Mol. Cell. Biol. 30:2787-98

Abstract

Although the BRCA1 tumor suppressor has been implicated in many cellular processes, the biochemical mechanisms by which it influences these diverse pathways are poorly understood. The only known enzymatic function of BRCA1 is the E3 ubiquitin ligase activity mediated by its highly conserved RING domain. In vivo, BRCA1 associates with the BARD1 polypeptide to form a heterodimeric BRCA1/BARD1 complex that catalyzes autoubiquitination of BRCA1 and trans ubiquitination of other protein substrates. In most cases, BRCA1-dependent ubiquitination generates polyubiquitin chains bearing an unconventional K6 linkage that does not appear to target proteins for proteasomal degradation. Since ubiquitin-dependent processes are usually mediated by cellular receptors with ubiquitin-binding motifs, we screened for proteins that specifically bind autoubiquitinated BRCA1. Here we report that the UBXN1 polypeptide, which contains a ubiquitin-associated (UBA) motif, recognizes autoubiquitinated BRCA1. This occurs through a bipartite interaction in which the UBA domain of UBXN1 binds K6-linked polyubiquitin chains conjugated to BRCA1 while the C-terminal sequences of UBXN1 bind the BRCA1/BARD1 heterodimer in a ubiquitin-independent fashion. Significantly, the E3 ligase activity of BRCA1/BARD1 is dramatically reduced in the presence of UBXN1, suggesting that UBXN1 regulates the enzymatic function of BRCA1 in a manner that is dependent on its ubiquitination status.

Links

PubMed PMC2876507 Online version:10.1128/MCB.01056-09

Keywords

Antigens, Neoplasm/genetics; Antigens, Neoplasm/metabolism; BRCA1 Protein/genetics; BRCA1 Protein/metabolism; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell Line; Humans; Polyubiquitin/metabolism; Protein Multimerization; Protein Structure, Tertiary; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism; Ubiquitination

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:BRCA1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q04323

F

Seeded From UniProt

complete

HUMAN:UBXN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99728

F

Seeded From UniProt

complete

HUMAN:UBXN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P38398

F

Seeded From UniProt

complete

HUMAN:UBXN1

involved_in

GO:0032435: negative regulation of proteasomal ubiquitin-dependent protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBXN1

involved_in

GO:0031397: negative regulation of protein ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBXN1

enables

GO:0071796: K6-linked polyubiquitin modification-dependent protein binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:BARD1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q04323

F

Seeded From UniProt

complete

HUMAN:BARD1

part_of

GO:0031436: BRCA1-BARD1 complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BARD1

contributes_to

GO:0004842: ubiquitin-protein transferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:BARD1

involved_in

GO:0085020: protein K6-linked ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BRCA1

enables

GO:0004842: ubiquitin-protein transferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:BRCA1

part_of

GO:0031436: BRCA1-BARD1 complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BRCA1

involved_in

GO:0051865: protein autoubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BRCA1

involved_in

GO:0085020: protein K6-linked ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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