Microtubule severing enzymes oligomerization and allostery: a tale of two domains DOI Open Access
Amanda C. Macke, Maria S. Kelly, Rohith Varikoti

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: July 27, 2022

Abstract Severing proteins are nanomachines from the AAA+ (ATPases associated with various cellular activities) superfamily whose function is to remodel largest filaments, microtubules. The standard machines adopt hexameric ring structures for functional reasons, while being primarily monomeric in absence of nucleotide. Both major severing proteins, katanin and spastin, believed follow this trend. However, studies proposed that they populate lower-order oligomers presence co-factors, which functionally relevant. Our simulations show preferred oligomeric assembly dependent on binding partners, type protein. Essential dynamics analysis predicts stability an oligomer strength interface between helical bundle domain (HBD) a monomer convex face nucleotide (NBD) neighboring monomer. Hot spots found region consisting HBD tip C-terminal (CT) helix only common element allosteric networks responding nucleotide, substrate, inter-monomer binding. Clustering indicates existence multiple pathways transition secondary structure monomers structure(s) it adopts oligomers.

Language: Английский

Combinatorial and antagonistic effects of tubulin glutamylation and glycylation on katanin microtubule severing DOI Creative Commons
Ewa Szczęsna, Elena A. Zehr,

Steven W. Cummings

et al.

Developmental Cell, Journal Year: 2022, Volume and Issue: 57(21), P. 2497 - 2513.e6

Published: Nov. 1, 2022

Language: Английский

Citations

33
CAMSAP1 role in orchestrating structure and dynamics of manchette microtubule minus-ends impacts male fertility during spermiogenesis DOI Creative Commons

Weichang Hu,

Rui Zhang, Honglin Xu

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(45)

Published: Oct. 30, 2023

The manchette is a crucial transient structure involved in sperm development, with its composition and regulation still not fully understood. This study focused on investigating the roles of CAMSAP1 CAMSAP2, microtubule (MT) minus-end binding proteins, regulating MTs, spermiogenesis, male fertility. loss CAMSAP1, but disrupts well-orchestrated process leading to abnormal elongation delayed removal, resulting deformed nuclei tails resembling oligoasthenozoospermia symptoms. We investigated underlying molecular mechanisms by purifying assemblies comparing them through proteomic analysis, results showed that absence disrupted proper localization key proteins (CEP170 KIF2A) at minus end, compromising structural integrity hindering MT depolymerization. These findings highlight significance maintaining homeostasis minus-ends for shaping morphology during late offering insights into infertility abnormalities.

Language: Английский

Citations

16
Dual-target inhibitors of colchicine binding site for cancer treatment DOI
Lu Lu, Keke Li,

Jiaxin Pu

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 274, P. 116543 - 116543

Published: May 31, 2024

Language: Английский

Citations

6
Microtubule-severing enzymes DOI Creative Commons
Stephanie L. Sarbanes, Elena A. Zehr, Antonina Roll‐Mecak

et al.

Current Biology, Journal Year: 2022, Volume and Issue: 32(19), P. R992 - R997

Published: Oct. 1, 2022

Language: Английский

Citations

22
Manipulation of Host Microtubule Networks by Viral Microtubule-Associated Proteins DOI Creative Commons
Dahee Seo, Don B. Gammon

Viruses, Journal Year: 2022, Volume and Issue: 14(5), P. 979 - 979

Published: May 6, 2022

Diverse DNA and RNA viruses utilize cytoskeletal networks to efficiently enter, replicate, exit the host cell, while evading immune responses. It is well established that microtubule (MT) network commonly hijacked by traffic sites of replication after entry promote egress from cell. However, mounting evidence suggests MT also a key regulator responses infection. At same time, have acquired mechanisms manipulate and/or usurp evade these Central most interactions with are virally encoded microtubule-associated proteins (MAPs) bind MTs directly or indirectly. These MAPs associate other viral cellular regulate various aspects network, including dynamics, MT-dependent transport via motor such as kinesins dyneins, regulation innate In this review, we examine how MAP facilitate evasion.

Language: Английский

Citations

18
The multifaceted roles of microtubule-associated proteins in the primary cilium and ciliopathies DOI Creative Commons
Jovana Deretic, Ezgi Odabasi, Elif Nur Firat‐Karalar

et al.

Journal of Cell Science, Journal Year: 2023, Volume and Issue: 136(23)

Published: Dec. 1, 2023

ABSTRACT The primary cilium is a conserved microtubule-based organelle that critical for transducing developmental, sensory and homeostatic signaling pathways. It comprises an axoneme with nine parallel doublet microtubules extending from the basal body, surrounded by ciliary membrane. exhibits remarkable stability, serving as skeleton of in order to maintain its shape provide tracks trafficking complexes. Although have been exhaustively characterized over years, less known about unique structural functional complexities axoneme. Recent work has yielded new insights into mechanisms which built proper length architecture, particularly regarding activity microtubule-associated proteins (MAPs). In this Review, we first summarize current knowledge composition specialized compartments cilium. Next, discuss mechanistic underpinnings how assembled, maintained disassembled through regulation axonemal microtubules. We conclude examining diverse localizations functions MAPs pathobiology diseases.

Language: Английский

Citations

10
Discovery of Novel Diaryl-Substituted Fused Heterocycles Targeting Katanin and Tubulin with Potent Antitumor and Antimultidrug Resistance Efficacy DOI

Fuhao Jiang,

Min Yu, Yuru Liang

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(14), P. 12118 - 12142

Published: July 12, 2024

Disrupting microtubule dynamics has emerged as a promising strategy for cancer treatment. However, drug resistance remains challenge hindering the development of microtubule-targeting agents. In this work, novel class diaryl substituted fused heterocycles were designed, synthesized, and evaluated, which demonstrated effective dual katanin tubulin regulators with antitumor activity. Following three rounds stepwise optimization, compound 21b, featuring 3H-imidazo[4,5-b]pyridine core, displayed excellent targeting capabilities on tubulin, along notable antiproliferative antimetastatic effects. Mechanistic studies revealed that 21b disrupts network in tumor cells, leading to G2/M cell cycle arrest apoptosis induction. Importantly, exhibited significant inhibition growth MDA-MB-231 A549/T xenograft models without evident toxicity side conclusion, presents mechanism disrupting dynamics, warranting further investigation dual-targeted agent potential antimultidrug properties.

Language: Английский

Citations

4
GPI transamidase complex is required for primordial germ cell migration and development in zebrafish DOI Creative Commons
Weiying Zhang,

Yaqi Li,

Jing Chen

et al.

Journal of Molecular Cell Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 31, 2024

Abstract Proteins without transmembrane domains could be anchored to the cell surface for regulating various biological processes when covalently linked glycosylphosphatidylinositol (GPI) molecules by GPI transamidase (GPIT) complex. However, it remains poorly understood whether and how GPIT complex affects primordial germ (PGC) development. In this study, we report important roles of in PGC migration development zebrafish embryos. Mutation pigu or pigk, both encoding essential subunits, resulted defective with ectopically located PGCs reduction counts. Notably, a detailed analysis filopodia revealed attenuated polarity distribution along direction mutant transplantation PGC-specific rescue experiments demonstrated that somatic cell-expressed Pigu are required migration. Furthermore, expression levels genes decreased derepression genes. Hence, propose plays critical role during

Language: Английский

Citations

3
Microtubule-binding domains in Katanin p80 subunit are essential for severing activity in C. elegans DOI Creative Commons
Eva Beaumale, Lucie Van Hove, Lionel Pintard

et al.

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(4)

Published: Feb. 8, 2024

Microtubule-severing enzymes (MSEs), such as Katanin, Spastin, and Fidgetin play essential roles in cell division neurogenesis. They damage the microtubule (MT) lattice, which can either destroy or amplify MT cytoskeleton, depending on cellular context. However, little is known about how they interact with their substrates. We have identified microtubule-binding domains (MTBD) required for Katanin function C. elegans. a heterohexamer of dimers containing catalytic subunit p60 regulatory p80, both are female meiotic spindle assembly. Here, we report that p80-like(MEI-2) dictates binding to MTs via two MTBDs composed basic patches. Substituting these patches reduces MTs, compromising its meiotic-spindle Structural alignments p80s from different species revealed evolutionarily conserved, even if specific amino acids involved vary. Our findings highlight critical importance (p80) providing complex.

Language: Английский

Citations

3
The quaternary question: Determining allostery in spastin through dynamics classification learning and bioinformatics DOI Open Access
Maria S. Kelly, Amanda C. Macke, Shehani Kahawatte

et al.

The Journal of Chemical Physics, Journal Year: 2023, Volume and Issue: 158(12)

Published: March 7, 2023

The nanomachine from the ATPases associated with various cellular activities superfamily, called spastin, severs microtubules during processes. To characterize functionally important allostery in we employed methods evolutionary information, to graph-based networks, machine learning applied atomistic molecular dynamics simulations of spastin its monomeric and functional hexameric forms, presence or absence ligands. Feature selection, using approaches, for transitions between states recognizes all regions that have been proposed as allosteric literature. analysis composition Markov State Model macrostates monomer, direction change top features transitions, indicate monomer favors binding ATP, which primes involved formation inter-protomer interfaces other protomer(s). Allosteric path graph built based on cross-correlations residues simulations, shows perturbations a hub specific pre-hydrolysis hexamer propagate throughout structure by passing through two obligatory regions: ATP pocket, pore loop 3, connects substrate site site. Our findings support model where changes terminal protomers due ligands play an active role force generation spastin. secondary structures are found be highly degenerative within network paths, also critical feature classification models, can guide design effectors enhance block signaling.

Language: Английский

Citations

7