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TitleStructure of the human ATAD2 AAA+ histone chaperone reveals mechanism of regulation and inter-subunit communication.
Journal, issue, pagesCommun Biol, Vol. 6, Issue 1, Page 993, Year 2023
Publish dateSep 28, 2023
AuthorsCarol Cho / Christian Ganser / Takayuki Uchihashi / Koichi Kato / Ji-Joon Song /
PubMed AbstractATAD2 is a non-canonical ATP-dependent histone chaperone and a major cancer target. Despite widespread efforts to design drugs targeting the ATAD2 bromodomain, little is known about the overall ...ATAD2 is a non-canonical ATP-dependent histone chaperone and a major cancer target. Despite widespread efforts to design drugs targeting the ATAD2 bromodomain, little is known about the overall structural organization and regulation of ATAD2. Here, we present the 3.1 Å cryo-EM structure of human ATAD2 in the ATP state, showing a shallow hexameric spiral that binds a peptide substrate at the central pore. The spiral conformation is locked by an N-terminal linker domain (LD) that wedges between the seam subunits, thus limiting ATP-dependent symmetry breaking of the AAA+ ring. In contrast, structures of the ATAD2-histone H3/H4 complex show the LD undocked from the seam, suggesting that H3/H4 binding unlocks the AAA+ spiral by allosterically releasing the LD. These findings, together with the discovery of an inter-subunit signaling mechanism, reveal a unique regulatory mechanism for ATAD2 and lay the foundation for developing new ATAD2 inhibitors.
External linksCommun Biol / PubMed:37770645 / PubMed Central
MethodsEM (single particle)
Resolution3.15 - 4.34 Å
Structure data

34468

8h3h

EMDB-34468, PDB-8h3h:
Human ATAD2 Walker B mutant, ATP state
Method: EM (single particle) / Resolution: 3.15 Å

36665

8juw

EMDB-36665, PDB-8juw:
Human ATAD2 Walker B mutant-H3/H4K5Q complex, ATP state
Method: EM (single particle) / Resolution: 3.79 Å

36666

8juy

EMDB-36666, PDB-8juy:
Human ATAD2 Walker B mutant-H3/H4K5Q complex, ATP state (Class II)
Method: EM (single particle) / Resolution: 4.34 Å

36667

8juz

EMDB-36667, PDB-8juz:
Human ATAD2 Walker B mutant-H3/H4K5Q complex, ATP state (Class III)
Method: EM (single particle) / Resolution: 4.29 Å

Chemicals

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

Source
  • homo sapiens (human)
KeywordsGENE REGULATION / Histone chaperone / AAA+ ATPase

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