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TitleCryo-EM reveals mechanistic insights into lipid-facilitated polyamine export by human ATP13A2.
Journal, issue, pagesMol Cell, Vol. 81, Issue 23, Page 4799-44809.e5, Year 2021
Publish dateDec 2, 2021
AuthorsAtsuhiro Tomita / Takashi Daiho / Tsukasa Kusakizako / Keitaro Yamashita / Satoshi Ogasawara / Takeshi Murata / Tomohiro Nishizawa / Osamu Nureki /
PubMed AbstractThe cytoplasmic polyamine maintains cellular homeostasis by chelating toxic metal cations, regulating transcriptional activity, and protecting DNA. ATP13A2 was identified as a lysosomal polyamine ...The cytoplasmic polyamine maintains cellular homeostasis by chelating toxic metal cations, regulating transcriptional activity, and protecting DNA. ATP13A2 was identified as a lysosomal polyamine exporter responsible for polyamine release into the cytosol, and its dysfunction is associated with Alzheimer's disease and other neural degradation diseases. ATP13A2 belongs to the P5 subfamily of the P-type ATPase family, but its mechanisms remain unknown. Here, we report the cryoelectron microscopy (cryo-EM) structures of human ATP13A2 under four different conditions, revealing the structural coupling between the polyamine binding and the dephosphorylation. Polyamine is bound at the luminal tunnel and recognized through numerous electrostatic and π-cation interactions, explaining its broad specificity. The unique N-terminal domain is anchored to the lipid membrane to stabilize the E2P conformation, thereby accelerating the E1P-to-E2P transition. These findings reveal the distinct mechanism of P5B ATPases, thereby paving the way for neuroprotective therapy by activating ATP13A2.
External linksMol Cell / PubMed:34798056 / PubMed Central
MethodsEM (single particle)
Resolution3.54 - 3.92 Å
Structure data

EMDB-32066, PDB-7vpi:
Cryo-EM structure of the human ATP13A2 (E1-ATP state)
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-32067, PDB-7vpj:
Cryo-EM structure of the human ATP13A2 (E1P-ADP state)
Method: EM (single particle) / Resolution: 3.54 Å

EMDB-32068, PDB-7vpk:
Cryo-EM structure of the human ATP13A2 (SPM-bound E2P state)
Method: EM (single particle) / Resolution: 3.92 Å

EMDB-32069, PDB-7vpl:
Cryo-EM structure of the human ATP13A2 (SPM-bound E2Pi state)
Method: EM (single particle) / Resolution: 3.78 Å

Chemicals

ChemComp-ACP:
PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / AMP-PCP, energy-carrying molecule analogue*YM

ChemComp-MG:
Unknown entry

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

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-ALF:
TETRAFLUOROALUMINATE ION

ChemComp-BEF:
BERYLLIUM TRIFLUORIDE ION

ChemComp-SPM:
SPERMINE / Spermine

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / ATP13A2 / PARK9 / P-type ATPase

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