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TitleCryo-EM structures of the ABCA4 importer reveal mechanisms underlying substrate binding and Stargardt disease.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 5902, Year 2021
Publish dateOct 8, 2021
AuthorsJessica Fernandes Scortecci / Laurie L Molday / Susan B Curtis / Fabian A Garces / Pankaj Panwar / Filip Van Petegem / Robert S Molday /
PubMed AbstractABCA4 is an ATP-binding cassette (ABC) transporter that flips N-retinylidene-phosphatidylethanolamine (N-Ret-PE) from the lumen to the cytoplasmic leaflet of photoreceptor membranes. Loss-of-function ...ABCA4 is an ATP-binding cassette (ABC) transporter that flips N-retinylidene-phosphatidylethanolamine (N-Ret-PE) from the lumen to the cytoplasmic leaflet of photoreceptor membranes. Loss-of-function mutations cause Stargardt disease (STGD1), a macular dystrophy associated with severe vision loss. To define the mechanisms underlying substrate binding and STGD1, we determine the cryo-EM structure of ABCA4 in its substrate-free and bound states. The two structures are similar and delineate an elongated protein with the two transmembrane domains (TMD) forming an outward facing conformation, extended and twisted exocytoplasmic domains (ECD), and closely opposed nucleotide binding domains. N-Ret-PE is wedged between the two TMDs and a loop from ECD1 within the lumen leaflet consistent with a lateral access mechanism and is stabilized through hydrophobic and ionic interactions with residues from the TMDs and ECDs. Our studies provide a framework for further elucidating the molecular mechanism associated with lipid transport and disease and developing promising disease interventions.
External linksNat Commun / PubMed:34625547 / PubMed Central
MethodsEM (single particle)
Resolution2.92 - 3.6 Å
Structure data

23617

7m1p

EMDB-23617, PDB-7m1p:
Human ABCA4 structure in the unbound state
Method: EM (single particle) / Resolution: 3.6 Å

23618

7m1q

EMDB-23618, PDB-7m1q:
Human ABCA4 structure in complex with N-ret-PE
Method: EM (single particle) / Resolution: 2.92 Å

Chemicals

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

ChemComp-HOH:
WATER / Water

ChemComp-HZL:
[(2S)-3-[2-[(E)-[(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenylidene]amino]ethoxy-oxidanyl-phosphoryl]oxy-2-[(Z)-octadec-9-enoyl]oxy-propyl] (Z)-octadec-9-enoate

ChemComp-MG:
Unknown entry

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / ABC transporter / importer / MEMBRANE PROTEIN

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