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TitleStructural insights into human ABCD3-mediated peroxisomal acyl-CoA translocation.
Journal, issue, pagesCell Discov, Vol. 10, Issue 1, Page 92, Year 2024
Publish dateSep 3, 2024
AuthorsYang Li / Zhi-Peng Chen / Da Xu / Liang Wang / Meng-Ting Cheng / Cong-Zhao Zhou / Yuxing Chen / Wen-Tao Hou /
PubMed AbstractHuman ABC transporters ABCD1-3 are all localized on the peroxisomal membrane and participate in the β-oxidation of fatty acyl-CoAs, but they differ from each other in substrate specificity. The ...Human ABC transporters ABCD1-3 are all localized on the peroxisomal membrane and participate in the β-oxidation of fatty acyl-CoAs, but they differ from each other in substrate specificity. The transport of branched-chain fatty acids from cytosol to peroxisome is specifically driven by ABCD3, dysfunction of which causes severe liver diseases such as hepatosplenomegaly. Here we report two cryogenic electron microscopy (cryo-EM) structures of ABCD3 bound to phytanoyl-CoA and ATP at resolutions of 2.9 Å and 3.2 Å, respectively. A pair of phytanoyl-CoA molecules were observed in ABCD3, each binding to one transmembrane domain (TMD), which is distinct from our previously reported structure of ABCD1, where each fatty acyl-CoA molecule strongly crosslinks two TMDs. Upon ATP binding, ABCD3 exhibits a conformation that is open towards the peroxisomal matrix, leaving two extra densities corresponding to two CoA molecules deeply embedded in the translocation cavity. Structural analysis combined with substrate-stimulated ATPase activity assays indicated that the present structures might represent two states of ABCD3 in the transport cycle. These findings advance our understanding of fatty acid oxidation and the molecular pathology of related diseases.
External linksCell Discov / PubMed:39223112 / PubMed Central
MethodsEM (single particle)
Resolution2.96 - 3.27 Å
Structure data

39703

8z0f

EMDB-39703, PDB-8z0f:
Cryo-EM structure of ATP-bound human very long-chain fatty acid ABC transporter ABCD3
Method: EM (single particle) / Resolution: 3.27 Å

39871

8z9x

EMDB-39871, PDB-8z9x:
Cryo-EM structure of Phytanoyl-CoA-bound human very long-chain fatty acid ABC transporter ABCD3
Method: EM (single particle) / Resolution: 2.96 Å

Chemicals

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


PDB Unreleased entry

PDB-1l1a: Unknown entry

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / very long-chain fatty / Peroxisome / ABC transporter

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