LetA defines a structurally distinct transporter family

Santarossa, Cristina C, Li, Yupeng, Yousef, Sara, Hasdemir, Hale S, Rodriguez, Carlos C, Haase, Max AB, Baek, Minkyung, Coudray, Nicolas, Pavek, John G, Focke, Kimber N, Silverberg, Annika L, Bautista, Carmelita, Yeh, Johannes T-H, Marty, Michael T, Baker, David, Tajkhorshid, Emad, Ekiert, Damian C, Bhabha, Gira (January 2026) LetA defines a structurally distinct transporter family. Nature. ISSN 0028-0836 (Public Dataset)

[thumbnail of 10.1038.s41586-025-09990-0.pdf] PDF
10.1038.s41586-025-09990-0.pdf - Published Version
Available under License Creative Commons Attribution Non-commercial.
Download (69MB)

Abstract

Membrane transport proteins translocate diverse cargos, ranging from small sugars to entire proteins, across cellular membranes1-3. A few structurally distinct protein families have been described that account for most of the known membrane transport processes4-6. However, many membrane proteins with predicted transporter functions remain uncharacterized. Here we determined the structure of Escherichia coli LetAB, a phospholipid transporter involved in outer membrane integrity, and found that LetA adopts a distinct architecture that is structurally and evolutionarily unrelated to known transporter families. LetA localizes to the inner membrane, where it is poised to load lipids into its binding partner, LetB, a mammalian cell entry (MCE) protein that forms an approximately 225 Å long tunnel for lipid transport across the cell envelope. Unexpectedly, the LetA transmembrane domains adopt a fold that is evolutionarily related to the eukaryotic tetraspanin family of membrane proteins, including transmembrane AMPA receptor regulatory proteins (TARPs) and claudins. Through a combination of deep mutational scanning, molecular dynamics simulations, AlphaFold-predicted alternative states and functional studies, we present a model for how the LetA-like family of membrane transporters facilitates the transport of lipids across the bacterial cell envelope.

Item Type: Paper
Subjects: organs, tissues, organelles, cell types and functions > tissues types and functions > membranes
organs, tissues, organelles, cell types and functions
organs, tissues, organelles, cell types and functions > tissues types and functions
CSHL Authors:
Communities: CSHL labs > Krainer lab
CSHL labs > Yeh Lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 21 January 2026
Date Deposited: 12 Feb 2026 13:34
Last Modified: 12 Feb 2026 13:34
Related URLs:
Dataset ID:
  • EMD-49148
  • EMD-49145
  • EMD-49146
  • EMD-49147
  • PDB: 9N8X
  • EMD-49152
  • EMD-49149
  • EMD-49150
  • EMD-49151
  • https://doi.org/10.6019/EMPIAR-13075
  • https://doi.org/10.6019/EMPIAR-13079
  • BioProject ID: PRJNA1221345
  • https://www.mavedb.org/experiments/urn:mavedb:00001252-a
  • https://zenodo.org/records/17343432
  • https://massive.ucsd.edu/ProteoSAFe/QueryMSV?id=MSV000096297
URI: https://repository.cshl.edu/id/eprint/42079

Actions (login required)

Administrator's edit/view item Administrator's edit/view item