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Publication Abstract from PubMed

Transcriptional activation of proinflammatory cytokines, mediated by tumor necrosis factor receptor-associated factors (TRAFs), is in part triggered by the degradation of the F-box protein, FBxl2, via an E3 ligase that contains another F-box protein, FBxo3. The ApaG domain of FBxo3 is required for the interaction with and degradation of FBxl2 [Mallampalli et al., (2013) J. Immunol. 191, 5247-55]. Here, we report the X-ray structure of the human FBxo3 ApaG domain, residues 278-407, at 2.0A resolution. Like bacterial ApaG proteins, this domain is characterized by a classic Immunoglobin/Fibronectin III-type fold, comprising a seven-stranded beta-sheet core, surrounded by four extended loops. Although cation binding had been proposed for bacterial ApaG proteins, no interactions with Mg2+ or Co2+ were detected for the human ApaG domain. In addition, dinucleotide polyphosphates, which have been reported to be second messengers in the inflammation response and targets of the bacterial ApaG-containing operon, are not bound by the human ApaG domain. In the context of the full-length protein, loop 1, comprising residues 294-303, is critical for the interaction with FBxl2. However, titration of the individual ApaG domain with a 15-mer FBxl2 peptide that was phosphorylated on the crucial T404, as well as the inability of the ApaG domain to interact with full-length FBxl2, assessed by co-immunoprecipitation, indicates that the ApaG domain alone is necessary, but not sufficient for binding and degradation of FBxl2. This article is protected by copyright. All rights reserved.

Crystal Structure and Interaction Studies of the Human FBxo3 ApaG Domain.,Krzysiak TC, Chen BB, Lear T, Mallampalli RK, Gronenborn AM FEBS J. 2016 Mar 24. doi: 10.1111/febs.13721. PMID:27010866^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.