It is concluded that the early emergence of the Rossmann fold reflects the chemical and physical constraints of protein folding, explaining both its profound antiquity and sustained longevity.
Koh Seya, Tatsuya Corlett, Hamza Giaffar et al.· bioRxiv· 0 citations
Vacuolar protein sorting-associated protein 4 (VPS4), which occurs in A and B isoforms in humans, is the only enzyme in the core endosomal sorting complex required for transport (ESCRT) machinery. Human VPS4 is considered a potential therapeutic target for activation in neurodegeneration, and for inhibition in cancer and HIV-1 infection. VPS4 assembles transiently into a hexamer, which then removes ESCRT-III subunits from polymeric assemblies by unfolding them and threading them through its central pore. The N-terminal MIT domain of VPS4 binds to C-terminal MIM motifs of ESCRT-III. Here, we determined the cryo-electron microscopy structure of the full-length human VPS4B hexamer in six-membered helical “spiral staircase” states. In one of these states, two of the six MIT domains are ordered and stabilize the hexamer by bridging the seam of the spiral staircase. Residues involved in seam-bridging contacts were found to be important for biochemical and cellular activity. The structures also revealed two modes for polypeptide occupancy of the central pore, one of which involves the MIT-AAA linker peptide. These observations suggest a mechanism for substrate-dependent hexamerization and priming of VPS4 for its ESCRT-III remodeling activity.
James H. Hurley, Yu-Chao Zhang, Shuixia Tan et al.· Research Square· 0 citations
The GFP fold has long been viewed as a specialized fluorescent scaffold found principally in marine animals. A structure-first search reveals a rare buried charge-network GFP-fold family spanning bacteria, fungi, and corals. Its members retain the eleven-stranded barrel and conserved chromophore-forming machinery but replace the canonical central tyrosine with methionine or other hydrophobic residues. Ancestral reconstruction supports a non-tyrosine state early in the lineage. Instead of a conventional chromophore, the barrel encloses an invariant five-residue network of two arginines, two glutamates, and Tyr168, whereas the chromophore-equivalent residue varies. The network is more conserved than the protein surface, occupies the most strongly constrained evolutionary sites, and remains formed across independent structure predictions and explicit-solvent molecular-dynamics trajectories. Fold-independent searches identify the same two-cation/two-anion/tyrosine network in 238 members of DUF2490, an unrelated outer-membrane beta-barrel family, consistent with convergent evolution of the buried network. These findings expand the known sequence and chemical space of the GFP barrel, although the biochemical function of the network remains unknown.
Analysis of oligomeric organization and structural plasticity of the periplasmic domain of polar-flagellum FliL from Vibrio alginolyticus and compared with detergent-solubilized full-length pofFliL suggests that such plasticity enables FliL to act as an adaptable scaffold for stator engagement and mechanosensitive remodeling of the motor.
Tatsuro Nishikino, N. Takekawa, Raymond N. Burton-Smith et al.· Molecular Microbiology· 0 citations
It is shown that GeoA cargo loading is mediated by repeating, short cargo loading peptides (CLPs), and that GeoA encapsulation provides benefits for enzyme activity and stability, and provides insights into a putative mode of cargo protein regulation via pore state modulation.
A. Fazal, Cassandra A. Dutcher, Michael P. Andreas et al.· bioRxiv· 0 citations
Robust oxygenic photosynthesis requires the efficient assembly and repair of the multi-subunit oxygen-evolving photosystem II (PSII) complex. Previous cryogenic electron microscopy (cryo-EM) structures of PSII assembly/disassembly intermediates have relied on the analysis of deletion mutants or removal of PSII subunits in vitro. Here we report the cryo-EM structures of naturally occurring dimeric PSII intermediates from the cyanobacterium Thermosynechococcus vestitus at a resolution of about 2.2 Å. These intermediates contain inactive dimers lacking the oxygen-evolving complex (OEC) and semi-active dimers with the OEC present in one of the two monomers. Our structural data provide a mechanism for how assembly and disassembly of the Mn4CaO5 cluster is coordinated with the binding and release of the extrinsic proteins: restructuring of the C-terminal tail of D1 subunit during assembly or disassembly of the Mn cluster triggers conformational changes in D2, CP47 and CP43 to drive the binding/release of the extrinsic proteins. A combination of structural and mass spectrometry data also suggests that the inactive PSII complexes may include damaged complexes containing oxidized D1-His332, a monodentate ligand to one of the Mn ions of the OEC. Photosystem II (PSII) is a light-driven multi-subunit membrane enzyme that catalyzes water oxidation at its Mn4CaO5 cluster. Here, the authors determine high-resolution cryo-EM structures of native PSII dimers lacking the Mn4CaO5 cluster, revealing structural changes associated with Mn cluster assembly and disassembly.
Ziyu Zhao, I. Vercellino, Julian P. Whitelegge et al.· Nature Communications· 0 citations
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MIT News · Artificial Intelligence· news.mit.eduAug 27, 2026
A new machine-learning framework aims to improve the success rate of computational protein design while moving away from results that reproduce sequences found in nature.
