bims-meglyc 2025-05-25 papers

Issue of 2025–05–25
two papers selected by
Silvia Radenkovic, UMC Utrecht

Nature. 2025 May 21.

Stepwise ATP translocation into the endoplasmic reticulum by human SLC35B1.

Ashutosh Gulati, Do-Hwan Ahn, Albert Suades, Yurie Hult, Gernot Wolf, So Iwata, Giulio Superti-Furga, Norimichi Nomura, David Drew.

ATP generated in the mitochondria is exported by an ADP/ATP carrier of the SLC25 family1. The endoplasmic reticulum (ER) cannot synthesize ATP but must import cytoplasmic ATP to energize protein folding, quality control and trafficking2,3. It was recently proposed that a member of the nucleotide sugar transporter family, termed SLC35B1 (also known as AXER), is not a nucleotide sugar transporter but a long-sought-after ER importer of ATP4. Here we report that human SLC35B1 does not bind nucleotide sugars but indeed executes strict ATP/ADP exchange with uptake kinetics consistent with the import of ATP into crude ER microsomes. A CRISPR-Cas9 cell-line knockout demonstrated that SLC35B1 clusters with the most essential SLC transporters for cell growth, consistent with its proposed physiological function. We have further determined seven cryogenic electron microscopy structures of human SLC35B1 in complex with an Fv fragment and either bound to an ATP analogue or ADP in all major conformations of the transport cycle. We observed that nucleotides were vertically repositioned up to approximately 6.5 Å during translocation while retaining key interactions with a flexible substrate-binding site. We conclude that SLC35B1 operates by a stepwise ATP translocation mechanism, which is a previously undescribed model for substrate translocation by an SLC transporter.

DOI: https://doi.org/10.1038/s41586-025-09069-w

Nat Rev Mol Cell Biol. 2025 May 19.

N-glycan-dependent protein maturation and quality control in the ER.

Kevin P Guay, Wen-Chuan Chou, Nathan P Canniff, Kylie B Paul, Daniel N Hebert.

The vast majority of proteins that traverse the mammalian secretory pathway become N-glycosylated in the endoplasmic reticulum (ER). The bulky glycan protein modifications, which are conserved in fungi and humans, act as maturation and quality-control tags. In this Review, we discuss findings published in the past decade that have rapidly expanded our understanding of the transfer and processing of N-glycans, as well as their role in protein maturation, quality control and trafficking in the ER, facilitated by structural insights into the addition of N-glycans by the oligosaccharyltransferases A and B (OST-A and OST-B). These findings suggest that N-glycans serve as reporters of the folding status of secretory proteins as they traverse the ER, enabling the lectin chaperones to guide their maturation. We also explore how the emergence of co-translational glycosylation and the expansion of the glycoproteostasis network in metazoans has expanded the role of N-glycans in early protein-maturation events and quality control.

DOI: https://doi.org/10.1038/s41580-025-00855-y