3PHD

Crystal structure of human HDAC6 in complex with ubiquitin

Summary for 3PHD

• Entry DOI: 10.2210/pdb3phd/pdb
• Related: 2ZNV 3C5K 3GV4 3NHE
• Descriptor: Histone deacetylase 6, Polyubiquitin, ZINC ION, ... (4 entities in total)
• Functional Keywords: hdac6, ubiquitin, structural genomics, structural genomics consortium, sgc, protein binding
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q9UBN7
• Total number of polymer chains: 8
• Total formula weight: 83187.19

Authors

Dong, A.,Qui, W.,Ravichandran, M.,Schuetz, A.,Loppnau, P.,Li, F.,Mackenzie, F.,Kozieradzki, I.,Ouyang, H.,Structural Genomics Consortium (SGC) (deposition date: 2010-11-03, release date: 2011-02-23, Last modification date: 2023-09-06)

Primary citation

Ouyang, H.,Ali, Y.O.,Ravichandran, M.,Dong, A.,Qiu, W.,Mackenzie, F.,Dhe-Paganon, S.,Arrowsmith, C.H.,Zhai, R.G.
Protein Aggregates Are Recruited to Aggresome by Histone Deacetylase 6 via Unanchored Ubiquitin C Termini.
J.Biol.Chem., 287:2317-2327, 2012

PubMed Abstract: The 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. The 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.

PubMed: 22069321
DOI: 10.1074/jbc.M111.273730

Experimental method

X-RAY DIFFRACTION (3 Å)