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PDBsum entry 3dbh
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Contents |
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522 a.a.
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432 a.a.
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86 a.a.
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76 a.a.
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References listed in PDB file
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Key reference
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Title
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Structural dissection of a gating mechanism preventing misactivation of ubiquitin by nedd8'S e1.
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Authors
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J.Souphron,
M.B.Waddell,
A.Paydar,
Z.Tokgöz-Gromley,
M.F.Roussel,
B.A.Schulman.
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Ref.
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Biochemistry, 2008,
47,
8961-8969.
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PubMed id
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Abstract
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Post-translational covalent modification by ubiquitin and ubiquitin-like
proteins (UBLs) is a major eukaryotic mechanism for regulating protein function.
In general, each UBL has its own E1 that serves as the entry point for a
cascade. The E1 first binds the UBL and catalyzes adenylation of the UBL's
C-terminus, prior to promoting UBL transfer to a downstream E2. Ubiquitin's Arg
72, which corresponds to Ala72 in the UBL NEDD8, is a key E1 selectivity
determinant: swapping ubiquitin and NEDD8 residue 72 identity was shown
previously to swap their E1 specificity. Correspondingly, Arg190 in the UBA3
subunit of NEDD8's heterodimeric E1 (the APPBP1-UBA3 complex), which corresponds
to a Gln in ubiquitin's E1 UBA1, is a key UBL selectivity determinant. Here, we
dissect this specificity with biochemical and X-ray crystallographic analysis of
APPBP1-UBA3-NEDD8 complexes in which NEDD8's residue 72 and UBA3's residue 190
are substituted with different combinations of Ala, Arg, or Gln. APPBP1-UBA3's
preference for NEDD8's Ala72 appears to be indirect, due to proper positioning
of UBA3's Arg190. By contrast, our data are consistent with direct positive
interactions between ubiquitin's Arg72 and an E1's Gln. However, APPBP1-UBA3's
failure to interact with a UBL having Arg72 is not due to a lack of this
favorable interaction, but rather arises from UBA3's Arg190 acting as a negative
gate. Thus, parallel residues from different UBL pathways can utilize distinct
mechanisms to dictate interaction selectivity, and specificity can be amplified
by barriers that prevent binding to components of different conjugation cascades.
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