3phd
Crystal structure of human HDAC6 in complex with ubiquitinCrystal structure of human HDAC6 in complex with ubiquitin
Structural highlights
Publication Abstract from PubMedThe aggresome pathway is activated when proteasomal clearance of misfolded proteins is hindered. Misfolded polyubiquitinated protein aggregates are recruited and transported to the aggresome via the microtubule network by a protein complex consisting of histone deacetylase 6 (HDAC6) and the dynein motor complex. Current model suggests that HDAC6 recognizes protein aggregates by binding directly to polyubiquitinated proteins. Here, we show that there are substantial amounts of unanchored ubiquitin in protein aggregates with solvent accessible C-termini. The ubiquitin binding domain (ZnF-UBP) of HDAC6 binds exclusively to the unanchored C-terminal diglycine motif of ubiquitin instead of conjugated polyubiquitin. The unanchored ubiquitin C-termini in the aggregates are generated in situ by aggregate-associated deubiquitinase ataxin-3. These results provide structural and mechanistic bases for the role of HDAC6 in aggresome formation and further suggest a novel ubiquitin-mediated signaling pathway, where the exposure of ubiquitin C-termini within protein aggregates enables HDAC6 recognition and transport to the aggresome. Protein aggregates are recruited to the aggresome by histone deacetylase 6 via unanchored ubiquitin C-termini.,Ouyang H, Ali YO, Ravichandran M, Dong A, Qiu W, Mackenzie F, Dhe-Paganon S, Arrowsmith CH, Zhai RG J Biol Chem. 2011 Nov 8. PMID:22069321[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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