Evidence for a credit-card-swipe mechanism in the human PC floppase ABCB4

Prescher, Martin; Bonus, Michele; Stindt, Jan; Keitel-Anselmino, Verena; Smits, Sander H. J.; Gohlke, Holger; Schmitt, Lutz

doi:10.1016/j.str.2021.05.013

Cited by 12 publications

(14 citation statements)

References 67 publications

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“…Other types of proposed mechanisms for ABC proteins include the peristaltic or credit card swipe mechanisms. For transporters operating with these mechanisms, the aforementioned two distinct conformations cannot be distinguished so promptly [ 8 , 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Collection and Prediction of ABC Transmembrane Protein Structures in the AI Era of Structural Biology

Tordai

Suhajda

Sillitoe

et al. 2022

IJMS

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The number of unique transmembrane (TM) protein structures doubled in the last four years, which can be attributed to the revolution of cryo-electron microscopy. In addition, AlphaFold2 (AF2) also provided a large number of predicted structures with high quality. However, if a specific protein family is the subject of a study, collecting the structures of the family members is highly challenging in spite of existing general and protein domain-specific databases. Here, we demonstrate this and assess the applicability and usability of automatic collection and presentation of protein structures via the ABC protein superfamily. Our pipeline identifies and classifies transmembrane ABC protein structures using the PFAM search and also aims to determine their conformational states based on special geometric measures, conftors. Since the AlphaFold database contains structure predictions only for single polypeptide chains, we performed AF2-Multimer predictions for human ABC half transporters functioning as dimers. Our AF2 predictions warn of possibly ambiguous interpretation of some biochemical data regarding interaction partners and call for further experiments and experimental structure determination. We made our predicted ABC protein structures available through a web application, and we joined the 3D-Beacons Network to reach the broader scientific community through platforms such as PDBe-KB.

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Section: Introductionmentioning

confidence: 99%

Comprehensive Collection and Prediction of ABC Transmembrane Protein Structures in the AI Era of Structural Biology

Tordai

Suhajda

Sillitoe

et al. 2022

IJMS

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“…Lipid flipping between the membrane bilayers is thought to be energetically costly because this process not only entails the translocation of the charged headgroup across the hydrophobic acyl-chain region of the bilayer but also the flipping of lipid molecules to align with the opposite membrane leaflet while an electric and hydrophobic seal is maintained. Cells accomplish membrane leaflet asymmetry by specialized transporters termed floppases 23 and flippases [24][25][26] . These proteins perform these challenging tasks by coupling lipid transport and flipping with energetically favorable processes such as ATP hydrolysis or shuttling ions down their electrochemical gradients [24][25][26][27] .…”

Section: Introductionmentioning

confidence: 99%

Lipid flipping in the omega-3 fatty-acid transporter

Nguyen

Lei

Lai

et al. 2022

Preprint

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Mfsd2a is the primary transporter for the docosahexaenoic acid (DHA), an omega-3 fatty acid, across the blood brain barrier (BBB). Defects in Mfsd2a are linked to ailments from behavioral, learning, and motor dysfunctions to severe microcephaly. Mfsd2a typically transports long-chain unsaturated fatty-acids, including DHA and α-Linolenic acid (ALA), that are attached to the zwitterionic lysophosphatidylcholine (LPC) headgroup. Even with two recently determined structures of Mfsd2a the molecular details of how this transporter performs the energetically unfavorable task of translocating and flipping lysolipids across the lipid bilayer remained unclear. Here, we report five single-particle cryo-EM structures of the Danio rerio Mfsd2a (drMfsd2a): in the inward-open conformation in the ligand-free state and bound to ALA-LPC at four unique positions along the substrate translocation pathway. These Mfsd2a snapshots detail the Na+-dependent flipping mechanism of the lipid-LPC from outer to inner membrane leaflet during ligand translocation through the Mfsd2a substrate tunnel and release for membrane integration on the cytoplasmic side. These results also map Mfsd2a mutants that disrupt lipid-LPC transport and are associated with known disease. Together these results provide a model for omega-3 fatty-acid transport and has the potential for the design of the delivery strategies for amphipathic drugs across the BBB.

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“…For transporters operating with these mechanisms, the aforementioned two distinct conformations cannot be distinguished so promptly. [8,29,30].…”

Section: Introductionmentioning

confidence: 99%

“…For transporters operating with these mechanisms, the aforementioned two distinct conformations cannot be distinguished so promptly. [8,29,30]. Although various structures of numerous ABC proteins were determined in the last years using cryo-electron microscopy, 25 of the 44 physiologically and pathologically important human ABC transmembrane proteins lack experimental structures in the PDB.…”

mentioning

confidence: 99%

Comprehensive collection and prediction of ABC transmembrane protein structures in the AI era of structural biology

Tordai

Suhajda

Sillitoe

et al. 2022

Preprint

View full text Add to dashboard Cite

The number of unique transmembrane (TM) protein structures doubled in the last four years that can be attributed to the revolution of cryo-electron microscopy. In addition, AlphaFold2 (AF2) also provided a large number of predicted structures with high quality. However, if a specific protein family is the subject of a study, collecting the structures of the family members is highly challenging in spite of existing general and protein domain-specific databases. Here, we demonstrate this and assess the applicability and usability of automatic collection and presentation of protein structures via the ABC protein superfamily. Our pipeline identifies and classifies transmembrane ABC protein structures using PFAM search and also aims to determine their conformational states based on special geometric measures, conftors. Since the AlphaFold database contains structure predictions only for single polypeptide chains, we performed AF2-Multimer predictions for human ABC half transporters functioning as dimers. Our AF2 predictions warn of possibly ambiguous interpretation of some biochemical data regarding interaction partners and call for further experiments and experimental structure determination. We made our predicted ABC protein structures available through a web application, and we joined the 3D-Beacons Network to reach the broader scientific community through platforms such as PDBe-KB.

show abstract

Evidence for a credit-card-swipe mechanism in the human PC floppase ABCB4

Abstract: Highlights d ABCB4 shows biphasic modulation for drug-like substrates analogous to ABCB1 d This indicates two distinct and autonomous substrate binding sites in ABCB4 d TMH1 is suggested to be involved in phosphatidylcholine lipid flop

Cited by 12 publications

References 67 publications

Comprehensive Collection and Prediction of ABC Transmembrane Protein Structures in the AI Era of Structural Biology

Comprehensive Collection and Prediction of ABC Transmembrane Protein Structures in the AI Era of Structural Biology

Lipid flipping in the omega-3 fatty-acid transporter

Comprehensive collection and prediction of ABC transmembrane protein structures in the AI era of structural biology

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