To assess whether LetA is evolutionarily related to known transporter families, we performed a structure-based search of the Protein Data Bank (PDB) using Foldseek37. We were unable to identify structural similarity to known transporter folds, suggesting that LetA represents a new type of membrane transport protein. However, this search revealed that an individual LetA TMD is structurally related to the tetraspanin superfamily of integral membrane proteins in eukaryotes. The LetA TMD most closely resembles TARPs and claudins, which have structurally equivalent β-sheets in their extracytoplasmic regions with 3–5 β-strands, and is more distantly related to VKOR and tetraspanin itself (Fig. 2h,i and Extended Data Fig. 3c,d). All of these proteins share a common topology in the TM helices, but only LetA contains ZnR domains, and is arranged as a pseudodimer with two consecutive tetraspanin-like domains. Functionally, the eukaryotic proteins are highly divergent, and none is known to exhibit transporter activity. Tetraspanins are involved in membrane organization via the formation of microdomains that serve to recruit binding partners, often involved in signal transduction38. TARPs regulate ion channel function in neurons39, claudins function in cell–cell adhesion40 and VKOR is involved in the recycling of oxidized vitamin K1 (ref. 41). Both tetraspanin and VKOR contain lipid-binding sites for cholesterol42 and vitamin K1 (ref. 41), respectively, roughly in regions corresponding to the periplasmic pocket in LetA, which is a possible substrate-binding site (Extended Data Fig. 3e).
To explore evolutionary relationships between LetA and proteins whose structures have yet to be experimentally characterized, we carried out a Foldseek search of the AlphaFold database of predicted protein structures. In addition to bacterial LetA-like proteins, this search revealed potential uncharacterized structural homologues of full-length LetA that are present in some parasites and marine protists (Extended Data Fig. 3f). The AlphaFold predictions resemble LetA, but lack ZnR domains. As MCE proteins are generally restricted to double-membraned bacteria and photosynthetic eukaryotes, it is unclear how LetA-like proteins function in parasites and marine protists. However, LetA-like proteins identified in kinetoplastids and dinoflagellates appear to be fused to an extracytoplasmic β-jellyroll domain (Extended Data Fig. 3f), reminiscent of the bridge-like lipid transport domains of VPS13 (ref. 43), YhdP44 and the LPS exporter45. Thus, these distantly related LetA relatives may mediate the transport of lipids in some eukaryotes via bridge-like proteins instead of MCE tunnels. Together, these analyses place LetA and LetA-like proteins in the tetraspanin superfamily, which was previously thought to be a eukaryotic innovation38, but we show to be present in prokaryotes as well.
Santarossa, C.C., Li, Y., Yousef, S. et al. LetA defines a structurally distinct transporter family.
Nature (2026). https://doi.org/10.1038/s41586-025-09990-0
https://doi.org/10.1038/s41586-025-09990-0 bu içeriği en az 2000 kelime olacak şekilde ve alt başlıklar ve madde içermiyecek şekilde ünlü bir science magazine için İngilizce olarak yeniden yaz. Teknik açıklamalar içersin ve viral olacak şekilde İngilizce yaz. Haber dışında başka bir şey içermesin. Haber içerisinde en az 12 paragraf ve her bir paragrafta da en az 50 kelime olsun. Cevapta sadece haber olsun. Ayrıca haberi yazdıktan sonra içerikten yararlanarak aşağıdaki başlıkların bilgisi var ise haberin altında doldur. Eğer bilgi yoksa ilgili kısmı yazma.:
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Santarossa, C.C., Li, Y., Yousef, S. et al. LetA defines a structurally distinct transporter family.
Nature (2026). https://doi.org/10.1038/s41586-025-09990-0
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41586-025-09990-0
Keywords
Tags: eukaryotic integral membrane proteinsfunctional divergence of transport proteinsLetA TMD structureLetA transporter familymembrane microdomains and signalingmembrane transport proteinsstructural similarity in transportersTARPs and claudins functionstetraspanin superfamilytransport protein evolutionZnR domains in transportersβ-sheets in membrane proteins
