In:
PLOS Biology, Public Library of Science (PLoS), Vol. 19, No. 12 ( 2021-12-8), p. e3001474-
Abstract:
Endoplasmic reticulum–associated degradation (ERAD) is a protein quality control pathway of fundamental importance to cellular homeostasis. Although multiple ERAD pathways exist for targeting topologically distinct substrates, all pathways require substrate ubiquitination. Here, we characterize a key role for the UBE2 G2 B inding R egion (G2BR) of the ERAD accessory protein ancient ubiquitous protein 1 (AUP1) in ERAD pathways. This 27-amino acid (aa) region of AUP1 binds with high specificity and low nanomolar affinity to the backside of the ERAD ubiquitin-conjugating enzyme (E2) UBE2G2. The structure of the AUP1 G2BR (G2BR AUP1 ) in complex with UBE2G2 reveals an interface that includes a network of salt bridges, hydrogen bonds, and hydrophobic interactions essential for AUP1 function in cells. The G2BR AUP1 shares significant structural conservation with the G2BR found in the E3 ubiquitin ligase gp78 and in vitro can similarly allosterically activate ubiquitination in conjunction with ERAD E3s. In cells, AUP1 is uniquely required to maintain normal levels of UBE2G2; this is due to G2BR AUP1 binding to the E2 and preventing its rapid degradation. In addition, the G2BR AUP1 is required for both ER membrane recruitment of UBE2G2 and for its activation at the ER membrane. Thus, by binding to the backside of a critical ERAD E2, G2BR AUP1 plays multiple critical roles in ERAD.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001474
DOI:
10.1371/journal.pbio.3001474.g001
DOI:
10.1371/journal.pbio.3001474.g002
DOI:
10.1371/journal.pbio.3001474.g003
DOI:
10.1371/journal.pbio.3001474.g004
DOI:
10.1371/journal.pbio.3001474.g005
DOI:
10.1371/journal.pbio.3001474.g006
DOI:
10.1371/journal.pbio.3001474.g007
DOI:
10.1371/journal.pbio.3001474.g008
DOI:
10.1371/journal.pbio.3001474.t001
DOI:
10.1371/journal.pbio.3001474.t002
DOI:
10.1371/journal.pbio.3001474.s001
DOI:
10.1371/journal.pbio.3001474.s002
DOI:
10.1371/journal.pbio.3001474.s003
DOI:
10.1371/journal.pbio.3001474.s004
DOI:
10.1371/journal.pbio.3001474.s005
DOI:
10.1371/journal.pbio.3001474.s006
DOI:
10.1371/journal.pbio.3001474.s007
DOI:
10.1371/journal.pbio.3001474.s008
DOI:
10.1371/journal.pbio.3001474.s009
DOI:
10.1371/journal.pbio.3001474.s010
DOI:
10.1371/journal.pbio.3001474.s011
DOI:
10.1371/journal.pbio.3001474.s012
DOI:
10.1371/journal.pbio.3001474.s013
DOI:
10.1371/journal.pbio.3001474.s014
DOI:
10.1371/journal.pbio.3001474.s015
DOI:
10.1371/journal.pbio.3001474.s016
DOI:
10.1371/journal.pbio.3001474.r001
DOI:
10.1371/journal.pbio.3001474.r002
DOI:
10.1371/journal.pbio.3001474.r003
DOI:
10.1371/journal.pbio.3001474.r004
DOI:
10.1371/journal.pbio.3001474.r005
DOI:
10.1371/journal.pbio.3001474.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2126773-X
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