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Reposted by Matthias Wilmanns

Kate Beckham @kshbeckham.bsky.social · 03/08/2026

Happy to share our recent story on the Type VII secretion system. Here were present new insights into the regulation of secretion mediated by the central pore. Thanks to all authors involved in the work. 🙂

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Matthias Wilmanns @matthiaswilmanns.bsky.social · 02/08/2026

From fuzzy to ridig We are pleased to share a new paper entitled “Intrinsic flexibility of the Type VII secretion central pore is required for substrate translocation”, published now in www.biorxiv.org/content/10.6... Great thanks to all contributing authors for their outstanding work.

In pathogenic mycobacteria up to five Type VII secretion systems serve as gates for substrate transport between the pathogen and the infected host. Recent high-resolution structures of these systems have revealed a complex architecture with separate sections facing the periplasm, crossing the inner cell wall membrane, and facing the cytosol. Substrate translocation occurs through a central pore that is formed by the inner transmembrane helices of the EccC subunits,

Despite conservation of the overall structural scaffold, an unexpected level of diversity has been observed, including variable assemblies, symmetries and subunit compositions. These differences also affect the central pore, which appears to be fuzzy, in sharp contrast to rigid transmembrane helices from other subunits surrounding it. This diversity has provoked hypotheses about additional features for establishing functional Type VII secretion.

To address this question, we have probed a series of mutants of residues involved in pore formation in one of the Type VII secretion systems (ESX-5) using secretion assays. We found that most of them impair its function. By in addition solving the single particle cryo-EM structure of one of these mutants in which an invariant proline was mutated, we discovered an unexpected rigidification of the pore. In this ESX-5 variant, the pore is formed by stalagmite-like structures from the inner transmembrane helices of the mutated EccC subunit.

Taken together, our data demonstrate that the pore’s intrinsic plasticity is essential to the system’s ability for substrate translocation. Our findings point to the importance of investigating both the structural and associated dynamic properties of functional Type VII machineries.

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Matthias Wilmanns @matthiaswilmanns.bsky.social · 13/06/2026

We are delighted to share share a new paper on the structure of a mycobacterial short chain/long chain hybrid acyl‑CoA carboxylase with an amazing architecture, now published in www.nature.com/articles/s42... Big thanks to all contributors and collaborators.

Pathogenic mycobacteria have an unusually large number of acyl-CoA carboxylase complexes with broad substrate diversity. These enzymes carboxylate acyl-CoA esters of various length, thus providing the building blocks for long and complex fatty acids. In pathogenic mycobacteria, one of the key products is mycolic acid, which is a distinct component of the cell envelope.

To uncover the conundrum of multiple and non-matching genes of still unidentified acyl‑CoA carboxylase complexes, we used an endogenous pulldown approach to capture biotinylated protein complexes. Unexpectedly we found an acyl‑CoA carboxylase complex consisting of one biotin carboxylase subunit (AccA3), two related carboxyl transferase subunits (AccD4, AccD5) and a previously uncharacterized subunit (AccD5). Enzymatic product analysis revealed distinct activities for short-chain acyl-CoAs and another one for long-chain acyl-CoAs, consistent with the presence of two related acyl‑CoA transferase subunits. High-resolution structures of this complex with and without short- and long-chain substrates revealed an asymmetric overall architecture with (AccA3)4/(AccD4)2/(AccD5)4/(AccE5)2 stoichiometry. Various unique and unprecedented features are described in the paper. They are amazing and stunning! 😳 😳 😳

The original idea for this project came from Edukondalu Mullapudi from our previous group, and Edu was also the one who carried out all the structural biology work. The project has been in collaboration with the lab of Luiz Pedro Carvalho, in which the biochemical assays were carried out. Big thanks to all involved into this project. 😊 😊 😊

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Matthias Wilmanns @matthiaswilmanns.bsky.social · 13/12/2025

@nishitgoradia.bsky.social, previous postdoc at @embl.org, and Stefan Werner from the University Hamburg Clinical Center received this year's Research Award of the Hamburg Cancer Society for their work published in www.nature.com/articles/s41467-024-49488-3. Our congratulations to both of you!

From left to right: Klaus Pantel (UKE), Stefan Werner (UKE), Nishit Goradia UKE, previously EMBL), Matthias Wilmanns (EMBL, UKE).

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Reposted by Matthias Wilmanns

John Rubinstein @johnrubinstein.bsky.social · 30/10/2025

New lab preprint! @zestytoast.bsky.social tagged a scarce mycobacterial protein in M. smegmatis with TwinStep but got… something? @kjamali.bsky.social's ModelAngelo built models & @martinsteinegger.bsky.social's FoldSeek IDed them as the biotin-containing MCC & LCC complexes 🧵 tinyurl.com/ukny4ptz

Cryo-EM maps and atomic models of the biotin-containing 3-methylcrotonyl-CoA carboxylase (MCC) complex and long-chain acyl-CoA carboxylase (LCC) complex

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Matthias Wilmanns @matthiaswilmanns.bsky.social · 18/11/2025

We are delighted to share a stunning short/long chain acyl-CoA carboxylase complex with a total of 16 subunits (8 x AccA3, 2 x AccD4, 4 x AccD5, 2 x AccE5). It hosts two related carboxylate transferase subunits (AccD4, AccD5). Our story is now on www.biorxiv.org/content/10.1101/2025.11.15.688623v1

biorxiv.org

Architecture of an asymmetric mycobacterial short chain/long chain acyl-CoA carboxylase

Endogenous extraction has revealed a mycobacterial hybrid acyl-CoA carboxylase (ACCase) complex exhibiting distinct long-chain (LC) and short-chain (LC) acyl-CoA carboxyl transferase (CT) activities. ...

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Matthias Wilmanns @matthiaswilmanns.bsky.social · 03/09/2025

We are excited to share our latest work, where we unravel the structural and functional secrets of the once-mysterious protein Pex8 revealing how it controls the peroxisomal cargo import receptor Pex5. Read more here: www.biorxiv.org/content/10.1101/2025.08.30.673231v1

Ensemble model of the full length Pex5 receptor (different blue color) in complex with Pex8 (green colors).

Key Findings:

Pex8 binds to a novel site on the mostly unfolded N-terminal region of the Pex5 receptor. This interaction is essential for peroxisomal protein import.

Computational modelling reveals the formation of an assembly with the trimeric peroxisomal E3-ubiquitin ligase.

We propose that this action positions the Pex5 receptor for its recycling, a step essential for the entire protein import process.

Why this matters:

Peroxisomes rely entirely on the import of folded proteins to function. Impaired peroxisome function is linked to severe disorders, and recent data show their crucial roles in carcinogenesis and the immune response. Our work elevates Pex8 from an enigma to a central player in this critical biological process.

Read the full story and see the structures here: https://www.biorxiv.org/content/10.1101/2025.08.30.673231v1

#CellBiology #StructuralBiology #Peroxisome #ProteinImport #bioRxiv #Biochemistry

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Matthias Wilmanns @matthiaswilmanns.bsky.social · 28/02/2025

How is nitrogen built into metabolites? Mother nature has invented an amazing set of enzymes, called glutamine amidotransferases, by first generating ammonia and then building it into diverse metabolites. Here is our newest contribution, published in ACS Catalysis doi.org/10.1021/acsc....

doi.org

Activity Regulation of a Glutamine Amidotransferase Bienzyme Complex by Substrate-Induced Subunit Interface Expansion

Glutamine amidotransferases are multienzyme machineries in which reactive ammonia is generated by a glutaminase and then transferred through a sequestered protein tunnel to a synthase active site for ...

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