View source for 3phd


==Crystal structure of human HDAC6 in complex with ubiquitin==
<StructureSection load='3phd' size='340' side='right' caption='[[3phd]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3phd]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3PHD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3PHD FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3c5k|3c5k]], [[3gv4|3gv4]], [[2znv|2znv]], [[3nhe|3nhe]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HDAC6, KIAA0901, JM21 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), UBB, UBA52, UBCEP2, UBC, RPS27A, UBA80, UBCEP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_deacetylase Histone deacetylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.98 3.5.1.98] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3phd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3phd OCA], [http://pdbe.org/3phd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3phd RCSB], [http://www.ebi.ac.uk/pdbsum/3phd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3phd ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/HDAC6_HUMAN HDAC6_HUMAN]] Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes (By similarity). Plays a central role in microtubule-dependent cell motility via deacetylation of tubulin.<ref>PMID:12024216</ref> <ref>PMID:17846173</ref>   In addition to its protein deacetylase activity, plays a key role in the degradation of misfolded proteins: when misfolded proteins are too abundant to be degraded by the chaperone refolding system and the ubiquitin-proteasome, mediates the transport of misfolded proteins to a cytoplasmic juxtanuclear structure called aggresome. Probably acts as an adapter that recognizes polyubiquitinated misfolded proteins and target them to the aggresome, facilitating their clearance by autophagy.<ref>PMID:12024216</ref> <ref>PMID:17846173</ref>  [[http://www.uniprot.org/uniprot/UBB_HUMAN UBB_HUMAN]] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.<ref>PMID:16543144</ref> <ref>PMID:19754430</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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. 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<ref>PMID:22069321</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3phd" style="background-color:#fffaf0;"></div>

==See Also==
*[[Histone deacetylase|Histone deacetylase]]
*[[Ubiquitin|Ubiquitin]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Histone deacetylase]]
[[Category: Human]]
[[Category: Dong, A]]
[[Category: Kozieradzki, I]]
[[Category: Li, F]]
[[Category: Loppnau, P]]
[[Category: Mackenzie, F]]
[[Category: Ouyang, H]]
[[Category: Qui, W]]
[[Category: Ravichandran, M]]
[[Category: Structural genomic]]
[[Category: Schuetz, A]]
[[Category: Hdac6]]
[[Category: Protein binding]]
[[Category: Sgc]]
[[Category: Ubiquitin]]