An iris-like pore for protein import into peroxisomes
Authors: D. He, Y. Gao, T. Rapoport
Abstract
Peroxisomes are ubiquitous, membrane-bound organelles that house essential metabolic enzymes imported from the cytosol in a folded and sometimes oligomeric state. Mobile receptors, such as PEX5, ferry cargo through a tyrosine/glycine (YG)-rich selective phase formed by PEX13 within the membrane, but how folded proteins of different sizes cross the membrane remains unknown. Here we report structures of the channel that mediates cargo import. Twelve PEX13 molecules assemble into a pore formed by a ring of tilted amphipathic helices in alternating orientations. Hydrophobic faces contact the lipid bilayer, whereas hydrophilic faces line the pore containing the YG phase. Pairs of oppositely oriented helices can slide relative to neighboring pairs and thereby alter the helix tilt angle, enabling iris-like dilation of the pore from ~52 Angstrom in the resting state to ~70 Angstrom, sufficient to accommodate the PEX5 receptor carrying small cargo. Translocation of the largest cargo requires further widening to ~100 Angstrom, a state supported by AlphaFold modeling and disulfide crosslinking. Our findings suggest that the channel provides an adaptive conduit for folded proteins of varying sizes, a mechanism distinct from other known modes of protein translocation.
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Peroxisome quality control is gated by a dynamic ATF6α–ABCD3 tetherC. Noddings, Rukmini Mukherjee, Carsten Peukert et al. · 2026 · bioRxiv · preprint, not peer reviewed · Not summarized yet
Peroxisome quality control is regulated through an ATF6α–ABCD3 tether, rather than through the PEX13 pore that imports folded proteins.
Abstract
The endoplasmic reticulum (ER) coordinates protein folding and lipid biosynthesis, while peroxisomes govern fatty-acid catabolism and redox balance. However, little is known about the mechanisms by which these organelles communicate. Here we show that activating transcription factor 6 (ATF6α), a cytoprotective ER-resident sensor of the unfolded protein response (UPR)1–4, forms a molecular tether that zippers the ER and peroxisomes together at a 23-nm intermembrane distance. ATF6α achieves this by inserting a short segment of its unstructured N-terminal cytosolic tail into the solvated transmembrane cavity of the peroxisomal ABC-type lipid transporter ABCD3, trapping it in an off-state. This …
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Cotranslational membrane protein biogenesis by an EMC-bound translocon.Madeline G. Rollins, Josephine Tang, Yu Wan et al. · 2026 · Nature Structural & Molecular Biology · Not summarized yet
Cotranslational membrane protein biogenesis examines ER translocons that insert nascent chains, not peroxisomal import of folded cargo.
Abstract
Secretory and membrane protein biogenesis occurs at ribosome-bound translocons in the endoplasmic reticulum (ER) membrane. Translocons consist of the Sec61 protein-conducting channel and various maturation factors including chaperones, modification enzymes and membrane insertases, which assemble dynamically in response to the biogenesis needs of a nascent polypeptide. In human cells, nascent multipass membrane proteins utilize the ER membrane protein complex (EMC) and the multipass translocon (MPT), but how these factors are deployed during biogenesis is unknown. Here we combine selective ribosome profiling, cryo-electron tomography and site-specific photocrosslinking to reveal the substrate…
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Structure and function of the DFCP1 membrane barrier responsible for ER microdomain organization in lysosome repairZhi-Cheng Cui, Karen Palacio-Rodríguez, Eric Herrmann et al. · 2026 · bioRxiv · preprint, not peer reviewed · Not summarized yet
DFCP1 forms a membrane coat that organizes ER microdomains during lysosome repair, rather than an adjustable protein-import pore.
Abstract
The endoplasmic reticulum (ER) forms specialized microdomains that organize autophagy, lipid droplet formation, and the repair of damaged lysosomes. The PI3P-binding protein DFCP1/ZFYVE1 marks these microdomains, raising the question as to whether and how one protein could define such a subcompartment. Here we determine the structure of full-length human DFCP1 bound to membranes by cryo-electron tomography and single-particle cryo-electron microscopy. DFCP1 assembles into a helical coat, built from tetramers that stack around a constricted membrane tube. Its ATPase domains form the organizing core of the helix, while its ER-targeting domains insert deeply into the outer leaflet, and its FYVE…
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Giant Vesicle Platform for Synthetic Endoplasmic Reticulum NetworksCade Vallero, Shreya Pramanik, Tsu-Wang Sun et al. · 2026 · bioRxiv · preprint, not peer reviewed · Not summarized yet
Giant vesicles are used to build synthetic ER networks, addressing membrane morphology rather than protein import through PEX13.
Abstract
The endoplasmic reticulum (ER) is a membrane-bound organelle found in all eukaryotic cells. This organelle has a fascinating morphology, which involves a network of membrane nanotubes and three-way junctions connecting three nanotubes. Previous reconstitution studies were based on proteo-liposomes with a size of 100 to 200 nanometers, using electron microscopy as the main method to image the resulting membrane morphologies. These studies revealed the importance of membrane GTPases, that is, membrane proteins that hydrolyse GTP. Here, we introduce an alternative platform for the formation of synthetic ER networks starting from giant unilamellar vesicles with a typical size of 10 mirometers an…
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A selectivity filter in Tim17 mediates intramitochondrial protein sortingAnnika Egeler, Sanjoy Paul, Rosario Valenti et al. · 2026 · Nature Communications · Not summarized yet
Tim17's selectivity filter sorts proteins through the mitochondrial inner-membrane translocase, a different organelle import system.
Abstract
Mitochondria import hundreds of proteins into the matrix and the inner membrane (IM). The translocase of the IM of mitochondria (TIM23 complex) sorts these proteins using topogenic signals in their structure and directs them into the matrix or inserts them into the IM. How these signals are deciphered is unknown. Here we show that Tim17, the protein-conducting subunit of the TIM23 complex, contains a highly conserved selectivity filter for incoming proteins. Using a fluorescence-based sorting reporter, we identified the mitochondrial oxidoreductase Dmo2 (akin to DMAC1 in humans) as factor for intramitochondrial protein sorting. Molecular dynamics simulations show that a Dmo2-dependent disulf…
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A multimeric pore complex in the poxvirus core revealed by integrative structural analysisJia-Sui Liu, Simon Schäfer, Svenja Lehnung et al. · 2026 · Nature Communications · Not summarized yet
The poxvirus study resolves a pore for viral RNA exit, not a peroxisomal conduit for folded protein import.
Abstract
It has long been known that poxviruses transcribe more than a hundred early mRNAs within their viral core, yet how these transcripts exit the core remains unknown. Here, we combine cryo-electron tomography with deep-learning-based particle picking, subtomogram averaging, cross-linking mass spectrometry, and AlphaFold3 modeling to resolve the molecular architecture of a long-sought pore within the poxvirus core. The pore is formed by a heteromeric assembly of the viral proteins E8, E6, and L3, which together create a hollow hexameric tube spanning both the core wall and the surface-exposed palisade layer. Within the pore channel, we observe a rod-like density consistent with the viral RNA hel…
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Cryo-EM structure of a protein nanopore reveals lipid acyl chains as integral componentsM. Ashworth, Oliver W. Noble, Michael J. Plevin et al. · 2026 · Science Advances · Not summarized yet
The MspA study examines a membrane-embedded nanopore and its lipid contacts, not a pore that dilates for peroxisomal cargo.
Abstract
Nanopore-based technologies are revolutionizing nucleic acid sequencing and molecular sensing, yet the structural basis by which pore-forming proteins interact with lipid membranes remains poorly defined. The mycobacterial porin MspA is a benchmark biological nanopore owing to its exceptional stability and uniquely narrow constriction, but accurate structural information is limited to protein-only models. Here, we present a 2.5-angstrom resolution cryo–electron microscopy structure of the M2 mutant of MspA embedded in a phospholipid nanodisc, providing a high-resolution experimental observation of MspA in a lipid environment. The structure reveals an annular arrangement of extended lipid acy…
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Backbone and side chain 1H, 13C and 15N chemical shift assignment of the cargo-recognition domain MOTH of human TANGO1Jelena Auch, Anna Carlotta Peddinghaus, Raphael Stoll · 2026 · Biomolecular NMR Assignments · Not summarized yet
TANGO1's MOTH domain recognizes bulky secretory cargo for ER-to-Golgi export, rather than mediating peroxisomal import.
Abstract
The cellular export of large-sized proteins, such as collagen or fibrillin, necessitates a specialized transport pathway tailored towards their size. For collagen and possibly also other bulky proteins, the Transport ANd Golgi Organization 1 (TANGO1) protein plays a substantial role in the transfer from the Endoplasmic Reticulum (ER) to the Golgi apparatus. TANGO1 and related proteins organize the ER exit sites and generate large export structures within the cytosol while anchored to the ER membrane. In contrast to other proteins involved, TANGO1 features a folded domain in the ER lumen, which seems to be central for detecting cargos. This cargo-recognition domain has been shown to bind the …
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Updated on 2 November 2026.