Brief biology and pathophysiology of Tekt bundles

Cell Adhesion & Migration, Journal Year: 2025, Volume and Issue: 19(1)

Published: Feb. 13, 2025

Tektins, a family of microtubule-stabilizing proteins, are critical for cilia and flagella assembly in mammals. They maintain doublet microtubule stability ciliary/flagellar motility. Loss Tekt1–5 causes instability, impaired motility, diseases like infertility, retinal degeneration, Mainzer-Saldino syndrome, diabetic nephropathy. Pathophysiological stimuli regulate Tektin expression through transcriptional, posttranscriptional, translational, posttranslational modifications. This review summarizes the latest findings on functions their role diseases.

Language: Английский

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Trypanosome doublet microtubule structures reveal flagellum assembly and motility mechanisms

Science, Journal Year: 2025, Volume and Issue: 387(6739)

Published: March 13, 2025

The flagellum of Trypanosoma brucei drives the parasite’s characteristic screw-like motion and is essential for its replication, transmission, pathogenesis. However, molecular details this process remain unclear. Here, we present high-resolution (up to 2.8 angstrom) cryo–electron microscopy structures T. flagellar doublet microtubules (DMTs). Integrated modeling identified 154 different axonemal proteins inside outside DMT and, together with genetic proteomic interrogation, revealed conserved trypanosome-specific foundations assembly motility. We captured dynein motors in their pre–power stroke state. Comparing atomic models between pre– post–power strokes defined how structural changes drive sliding adjacent DMTs during beating. This study illuminates dynamics underlying motility identifies pathogen-specific consider therapeutic interventions targeting neglected diseases.

Language: Английский

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Structures of Native Doublet Microtubules from Trichomonas vaginalis Reveal Parasite-Specific Proteins

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 29, 2025

Abstract Doublet microtubules (DMTs) are flagellar components required for the protist Trichomonas vaginalis ( Tv ) to swim through human genitourinary tract cause trichomoniasis, most common non-viral sexually transmitted disease. Lack of structures ’s DMT -DMT) has prevented structure-guided drug design manage infection. Here, we determine 16 nm, 32 48 nm and 96 nm-repeat native Tv- at resolution ranging from 3.4 4.4 Å by cryogenic electron microscopy (cryoEM) built an atomic model entire -DMT. These show that -DMT is composed 30 different proteins, including α- β-tubulin, 19 microtubule inner proteins (MIPs) 9 outer proteins. While A-tubule simplistic compared DMTs other organisms, B-tubule features parasite-specific such as FAP40 FAP35. Notably, FAP35 form filaments near junctions, respectively, interface with stabilizing MIPs. This highlights diversity eukaryotic motility machineries provides a structural framework inform rational therapeutics against trichomoniasis.

Language: Английский

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The structure of basal body inner junctions from Tetrahymena revealed by electron cryo-tomography

The EMBO Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

Abstract The cilium is a microtubule-based eukaryotic organelle critical for many cellular functions. Its assembly initiates at basal body and continues as an axoneme that projects out of the cell to form functional cilium. This process tightly regulated. However, our knowledge molecular architecture mechanism limited. By applying cryo-electron tomography, we obtained structures inner junction in three regions from Tetrahymena : proximal, central core body, axoneme. We identified several protein components body. While few proteins are distributed throughout entire length organelle, restricted specific regions, forming intricate local interaction networks bolstering structural stability. examining POC1 knockout mutant, found triplet microtubule was destabilized, resulting defective structure. Surprisingly, axoneme-specific were “infiltrate” into mutant Our findings provide insight junctions, underscoring its precise spatial regulation.

Language: Английский

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Advancing Molecular Simulations: Merging Physical Models, Experiments, and AI to Tackle Multiscale Complexity

The Journal of Physical Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown, P. 3606 - 3615

Published: April 3, 2025

Proteins and protein complexes form adaptable networks that regulate essential biochemical pathways define cell phenotypes through dynamic mechanisms interactions. Advances in structural biology molecular simulations have revealed how systems respond to changes their environments, such as ligand binding, stress conditions, or perturbations like mutations post-translational modifications, influencing signal transduction cellular phenotypes. Here, we discuss computational approaches, ranging from dynamics (MD) AI-driven methods, are instrumental studying isolated molecules large assemblies. These techniques elucidate conformational landscapes, ligand-binding mechanisms, protein-protein interactions starting support the construction of multiscale realistic representations highly complex systems, up whole models. With cryo-electron microscopy, tomography, AlphaFold accelerating characterization networks, suggest integrating AI Machine Learning with MD methods will enhance fundamental understating for ever-increasing complexity, usher exciting possibilities predictive modeling behavior compartments even cells. advances indeed transforming biophysics chemical biology, offering new opportunities study biomolecular at atomic resolution.

Language: Английский

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Molecular architecture of the ciliary tip revealed by cryo-electron tomography

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 3, 2023

Cilia are essential organelles that protrude from the cell body. made of a microtubule-based structure called axoneme. In most types cilia, ciliary tip is distinct rest cilium. Here, we used cryo-electron tomography and subtomogram averaging to obtain ciliate

Language: Английский

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Structures, dynamics, complexes, and functions: From classic computation to artificial intelligence

Current Opinion in Structural Biology, Journal Year: 2024, Volume and Issue: 87, P. 102835 - 102835

Published: May 13, 2024

Computational approaches can provide highly detailed insight into the molecular recognition processes that underlie drug binding, assembly of protein complexes, and regulation biological functional processes. Classical simulation methods bridge a wide range length- time-scales typically involved in such Lately, automated learning artificial intelligence have shown potential to expand reach physics-based approaches, ushering possibility model even design complex architectures. The synergy between atomistic simulations AI is an emerging frontier with huge for advances structural biology. Herein, we explore various examples frameworks these providing select instances applications illustrate their impact on fundamental biomolecular problems.

Language: Английский

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Gene-deficient mouse model established by CRISPR/Cas9 system reveals 15 reproductive organ-enriched genes dispensable for male fertility

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: May 21, 2024

Since the advent of gene-targeting technology in embryonic stem cells, mice have become a primary model organism for investigating human gene function due to striking genomic similarities between two species. With introduction CRISPR/Cas9 system genome editing mice, pace loss-of-function analysis has accelerated significantly. This led identification numerous genes that play crucial roles male reproductive processes, including meiosis, chromatin condensation, flagellum formation testis, sperm maturation epididymis, and fertilization oviduct. Despite advancements, functions many genes, particularly those enriched tissues, remain largely unknown. In our study, we focused on 15 generated 13 gene-deficient [ 4933411K16Rik , Adam triple ( Adam20 Adam25 Adam39 ), BC048671 Cfap68 Gm4846 Gm4984 Gm13570 Nt5c1b Ppp1r42 Saxo4 Sh3d21 Spz1 Tektl1 ] elucidate their fertility. Surprisingly, all exhibited normal fertility natural breeding experiments, indicating these are not essential These findings important implications as they may help prevent other research laboratories from duplicating efforts generate knockout do demonstrate an apparent phenotype related By shedding light dispensability study contributes more efficient allocation resources exploration biology.

Language: Английский

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Structures of Native Doublet Microtubules from Trichomonas vaginalis Reveal Parasite-Specific Proteins as Potential Drug Targets

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 11, 2024

Doublet microtubules (DMTs) are flagellar components required for the protist

Language: Английский

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Structural determination and modeling of ciliary microtubules

Acta Crystallographica Section D Structural Biology, Journal Year: 2024, Volume and Issue: 80(4), P. 220 - 231

Published: March 7, 2024

The axoneme, a microtubule-based array at the center of every cilium, has been subject structural investigations for decades, but only recent advances in cryo-EM and cryo-ET have allowed molecular-level interpretation entire complex to be achieved. unique properties nine doublet microtubules central pair singlet that form including highly decorated tubulin lattice docking massive axonemal complexes, provide opportunities challenges sample preparation, 3D reconstruction atomic modeling. Here, approaches used axonemes are reviewed, while highlighting provided by latest generation AI-guided tools transforming biology.

Language: Английский

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