المؤلفون: Jiří Průša, Michal Cifra

المصدر: Data in Brief, Vol 52, Iss , Pp 109765- (2024)

مصطلحات موضوعية: Molecular dynamics, Electric field, Proteins, Microtubule, Kinesin, Computer applications to medicine. Medical informatics, R858-859.7, Science (General), Q1-390

الوصف: We present trajectories from non-equilibrium (in electric field) molecular dynamics (MD) simulations of a kinesin motor domain on tubulin heterodimers with two tubulin heterodimers forming neighbouring microtubule protofilaments. The trajectories are for no field (long equilibrium simulation), for four different electric field orientations (X, -X, Y, -Y) and for the X electric field at four different field strengths. We also provide a trajectory for larger simulation box. Our data enable to analyze the electric field effects on kinesin, which ultimately leads to kinesin detachment. This data set was used to understand the effect of electric field orientation and field strength on the kinetics and energetics of the electro-detachment of kinesin [1].

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2352340923008326Test; https://doaj.org/toc/2352-3409Test

الوصول الحر: https://doaj.org/article/75ab9579f7c5453fab15055294f2c387Test

المؤلفون: Chiba, Kyoko, Ori-McKenney, Kassandra M, Niwa, Shinsuke, McKenney, Richard J

المصدر: Cell Reports. 39(9)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biological Sciences, 1.1 Normal biological development and functioning, Underpinning research, Adaptor Proteins, Signal Transducing, Carrier Proteins, Humans, Kinesins, Microtubules, Motor Activity, CP: Molecular biology, dynein, kinesin, microtubule, motor protein, Medical Physiology, Biological sciences

الوصف: Kinesin-1 activity is regulated by autoinhibition. Intramolecular interactions within the kinesin heavy chain (KHC) are proposed to be one facet of motor regulation. The KHC also binds to the kinesin light chain (KLC), which has been implicated in both autoinhibition and activation of the motor. We show that the KLC inhibits the kinesin-microtubule interaction independently from the proposed intramolecular interaction within KHC. Cargo-adaptor proteins that bind the KLC stimulated processive movement, but the landing rate of activated kinesin complexes remained low. Mitogen-activated protein 7 (MAP7) enhanced motility by increasing the landing rate and run length of the activated kinesin motors. Our results support a model whereby the motor activity of the kinesin is regulated by synergistic inhibition mechanisms and that cargo-adaptor binding to the KLC releases both mechanisms. However, a non-motor MAP is required for robust microtubule association of the activated motor. Thus, human kinesin is regulated by synergistic autoinhibition and activation mechanisms.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/11j3t2ndTest

المؤلفون: Samia A. Elseginy

مصطلحات موضوعية: Protein Structure Prediction and Analysis, Molecular Biology, Biochemistry, Genetics and Molecular Biology, Life Sciences, Regulation and Function of Microtubules in Cell Division, Cell Biology, NMR Spectroscopy Techniques, Spectroscopy, Chemistry, Physical Sciences, Protein Structure Determination, Virtual screening, Allosteric regulation, Kinesin, Docking animal, Molecular dynamics, Mitosis, Small molecule, Ligand biochemistry, AutoDock, Scaffold protein, Computational biology, Biophysics, Biology, Biochemistry, Microtubule, Cell biology, Enzyme, Receptor, Signal transduction

الوصف: The kinesin spindle protein (Eg5) is a mitotic protein that plays an essential role in the formation of the bipolar spindles during the mitotic phase. Eg5 protein controls the segregation of the chromosomes in mitosis which renders it a vital target for cancer treatment. In this study our approach to identifying novel scaffold for Eg5 inhibitors is based on targeting the novel allosteric pocket (α4/α6/L11). Extensive computational techniques were applied using ligand-based virtual screening and molecular docking by two approaches, MOE and AutoDock, to screen a library of commercial compounds. We identified compound 8-(3-(1H-imidazol-1-ylpropylamino)-3-methyl-7-((naphthalen-3-yl)methyl)-1H-purine-2, 6 (3H,7H)-dione (compound 5) as a novel scaffold for Eg5 inhibitors. This compound inhibited cancer cell Eg5 ATPase at 2.37 ± 0.15 µM. The molecular dynamics simulations revealed that the identified compound formed stable interactions in the allosteric pocket (α4/α6/L11) of the receptor, indicating its potential ... : بروتين مغزل كينيسين (Eg5) هو بروتين فتيلي يلعب دورًا أساسيًا في تكوين المغزل ثنائي القطب خلال المرحلة الفتيلية. يتحكم بروتين Eg5 في فصل الكروموسومات في الانقسام المتساوي مما يجعله هدفًا حيويًا لعلاج السرطان. في هذه الدراسة، يعتمد نهجنا في تحديد سقالة جديدة لمثبطات Eg5 على استهداف الجيب التفارغي الجديد (α 4/α 6/L 11). تم تطبيق تقنيات حسابية واسعة النطاق باستخدام الفحص الافتراضي القائم على الترابط والالتحام الجزيئي من خلال نهجين، MOE و AutoDock، لفحص مكتبة من المركبات التجارية. حددنا المركب 8-( 3-( 1H -imidazol -1 - ylpropylamino )-3 - methyl -7 -(( naphthalen -3 - yl) methyl )-1 H - purine -2, 6 (3H ,7H )- dione (المركب 5) كسقالة جديدة لمثبطات Eg5. هذا المركب يثبط الخلايا السرطانية Eg5 ATPase عند 2.37 ± 0.15 ميكرومتر. كشفت محاكاة الديناميكيات الجزيئية أن المركب المحدد شكل تفاعلات مستقرة في الجيب التفارغي (α 4/α 6/L 11) للمستقبل، مما يشير إلى إمكاناته كمثبط جديد لـ Eg 5. ...

العلاقة: https://dx.doi.org/10.60692/7aggs-9n418Test

الإتاحة: https://doi.org/10.60692/etfe1-56d4210.60692/7aggs-9n418Test

المؤلفون: Young, Florence

المساهمون: Bullock, Simon

مصطلحات موضوعية: Axonal transport, Microtubule, Dynein, Kinesin, neuron, amyotrophic lateral sclerosis, frontotemporal dementia, neurodegenerative disease, C9orf72, molecular biology

الوصف: Understanding the etiology of neurodegenerative diseases and developing therapeutic strategies to tackle these conditions has become an increasingly important challenge for biomedical research. Neurons, with their extended axons and dendrites, rely on the integrity of the microtubule cytoskeleton and efficient axonal transport by the microtubule-based motors kinesin and dynein to maintain cell shape and function. Perturbation of the axonal transport machinery has been associated with various neurodegenerative diseases, including Alzheimer's disease, and certain forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS or motor neuron disease). However, the cellular mechanisms that lead to impaired transport in these diseases are poorly understood. In this work I focus on the most common heritable form of ALS/FTD, which is caused by an expansion in the gene C9orf72. Previous experiments indicated that the arginine-rich dipeptide repeats (DPRs) produced from the C9orf72 expansion can disrupt many cellular processes, including intracellular transport. However, the mechanism by which axonal transport is dysregulated in C9orf72- ALS/FTD and whether this occurs by direct or indirect inhibition by arginine-rich DPRs remained unknown. Here, I show using in vitro assays that dynein is recruited to the surface of liquid droplets consisting of arginine-rich DPRs and RNA, and stabilises these structures. I also demonstrate that the large, extended shape of dynein might be responsible for the motor's recruitment to the droplet surface. These data raise the possibility that sequestration of dynein complexes by arginine-rich DPR/RNA condensates, or stabilisation of these structures by dynein, contributes to C9orf72-ALS/FTD. I also use in vitro motility assays to show that the movement of purified kinesin-1 and dynein complexes along microtubules is directly inhibited by arginine-rich DPRs. I go on to demonstrate that expression of these peptides in the wing nerves of live adult Drosophila impedes axonal cargo trafficking. Accumulations of arginine-rich DPRs on the microtubule tracks lead to increased motor pausing and detachment in vitro. Arrest of transport is more frequently observed in patient-derived neurons and control neurons exposed to arginine-rich DPRs, lending support to the physiological relevance of my in vitro findings. The findings of my genetic interaction studies in Drosophila indicate that impaired microtubule- based transport contributes to the toxicity of arginine-rich DPRs. Additional experiments show that arginine-rich DPRs directly bind the C-terminal tail of tubulin and, in addition to impeding motor movement, dysregulate growth, nucleation and bundling of microtubules in vitro. Collectively, this work expands our understanding of the molecular mechanisms contributing to C9orf72-ALS/FTD. The discovery of microtubule-related processes that are perturbed by arginine-rich DPRs also paves the way for novel therapeutic strategies, including preventing the binding of arginine-rich DPRs to motors or the C-terminal tails of microtubules.

الوصول الحر: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.852793Test

المؤلفون: Yu Minghui, Xue Ao, Xu Hongdan, Wang Yan, Lin Xue, Yang Bo, Sun Huifeng, Zhang Ning

المصدر: Xin yixue, Vol 53, Iss 12, Pp 874-877 (2022)

مصطلحات موضوعية: axonal transport dysfunction, alzheimer’s disease, kinesin, microtubule, mitochondria, Medicine

الوصف: Alzheimer’s disease is known as one of the “top ten killers in the world”. Due to lack of effective therapy at present， early pathological changes have captivated widespread attention. Axonal transport dysfunction has been reported as an early pathological feature of many neurodegenerative diseases. However， multiple factors can cause axonal transport dysfunction. In this article， the relationship between axonal transport dysfunction caused by kinesins， microtubules and mitochondria and Alzheimer’s disease was discussed， aiming to provide new ideas for the prevention and treatment of Alzheimer’s disease by in-depth study on axonal transport mechanism of neure.

وصف الملف: electronic resource

العلاقة: https://www.xinyixue.cn/fileup/0253-9802/PDF/1672912128793-1957950978.pdfTest; https://doaj.org/toc/0253-9802Test

الوصول الحر: https://doaj.org/article/843e3f2f11724db0b176b07f5c6d2c32Test

المؤلفون: Budaitis, Breane G, Jariwala, Shashank, Reinemann, Dana N, Schimert, Kristin I, Scarabelli, Guido, Grant, Barry J, Sept, David, Lang, Matthew J, Verhey, Kristen J

مصطلحات موضوعية: COS Cells, Animals, Kinesin, Adenosine Triphosphate, Mutagenesis, Site-Directed, Protein Conformation, Protein Binding, Mutant Proteins, Molecular Dynamics Simulation, Chlorocebus aethiops, cell biology, cover-neck bundle, force, kinesin, microtubule, molecular biophysics, molecular motor, neck linker, none, structural biology, Mutagenesis, Site-Directed, Biochemistry and Cell Biology

الوصف: Kinesin force generation involves ATP-induced docking of the neck linker (NL) along the motor core. However, the roles of the proposed steps of NL docking, cover-neck bundle (CNB) and asparagine latch (N-latch) formation, during force generation are unclear. Furthermore, the necessity of NL docking for transport of membrane-bound cargo in cells has not been tested. We generated kinesin-1 motors impaired in CNB and/or N-latch formation based on molecular dynamics simulations. The mutant motors displayed reduced force output and inability to stall in optical trap assays but exhibited increased speeds, run lengths, and landing rates under unloaded conditions. NL docking thus enhances force production but at a cost to speed and processivity. In cells, teams of mutant motors were hindered in their ability to drive transport of Golgi elements (high-load cargo) but not peroxisomes (low-load cargo). These results demonstrate that the NL serves as a mechanical element for kinesin-1 transport under physiological conditions.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/49d0841zTest

المؤلفون: Verhey, Kristen J., Ryoma Ohi

المصدر: Journal of Cell Science; Mar2023, Vol. 136 Issue 5, p1-9, 9p

مصطلحات موضوعية: MOLECULAR motor proteins, MICROTUBULES, KINESIN, CELL physiology, ALLOSTERIC regulation, MICROTUBULE-associated proteins, TUBULINS

مستخلص: Microtubules are critical for a variety of important functions in eukaryotic cells. During intracellular trafficking, molecular motor proteins of the kinesin superfamily drive the transport of cellular cargoes by stepping processively along the microtubule surface. Traditionally, the microtubule has been viewed as simply a track for kinesin motility. New work is challenging this classic view by showing that kinesin-1 and kinesin-4 proteins can induce conformational changes in tubulin subunits while they are stepping. These conformational changes appear to propagate along the microtubule such that the kinesins can work allosterically through the lattice to influence other proteins on the same track. Thus, the microtubule is a plastic medium through which motors and other microtubule-associated proteins (MAPs) can communicate. Furthermore, stepping kinesin-1 can damage the microtubule lattice. Damage can be repaired by the incorporation of new tubulin subunits, but too much damage leads to microtubule breakage and disassembly. Thus, the addition and loss of tubulin subunits are not restricted to the ends of the microtubule filament but rather, the lattice itself undergoes continuous repair and remodeling. This work leads to a new understanding of how kinesin motors and their microtubule tracks engage in allosteric interactions that are critical for normal cell physiology. [ABSTRACT FROM AUTHOR]

: Copyright of Journal of Cell Science is the property of Company of Biologists Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Monroy, Brigette Y, Tan, Tracy C, Oclaman, Janah May, Han, Jisoo S, Simó, Sergi, Niwa, Shinsuke, Nowakowski, Dan W, McKenney, Richard J, Ori-McKenney, Kassandra M

المصدر: Developmental Cell. 53(1)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biological Sciences, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Animals, Biological Transport, Cell Movement, Cytoplasm, Dyneins, Kinesins, Microtubule-Associated Proteins, Microtubules, Protein Transport, MAP2, MAP7, MAP9, doublecortin, doublecortin-like kinase, dynein, kinesin, microtubule, microtubule-associated protein, tau, Medical and Health Sciences, Developmental Biology, Biochemistry and cell biology

الوصف: Many eukaryotic cells distribute their intracellular components asymmetrically through regulated active transport driven by molecular motors along microtubule tracks. While intrinsic and extrinsic regulation of motor activity exists, what governs the overall distribution of activated motor-cargo complexes within cells remains unclear. Here, we utilize in vitro reconstitution of purified motor proteins and non-enzymatic microtubule-associated proteins (MAPs) to demonstrate that MAPs exhibit distinct influences on the motility of the three main classes of transport motors: kinesin-1, kinesin-3, and cytoplasmic dynein. Further, we dissect how combinations of MAPs affect motors and unveil MAP9 as a positive modulator of kinesin-3 motility. From these data, we propose a general "MAP code" that has the capacity to strongly bias directed movement along microtubules and helps elucidate the intricate intracellular sorting observed in highly polarized cells such as neurons.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1h1949jcTest

المؤلفون: Ayushi Nair, Alosh Greeny, Rajalakshmi Rajendran, Mohamed A. Abdelgawad, Mohammed M. Ghoneim, Roshni Pushpa Raghavan, Sachithra Thazhathuveedu Sudevan, Bijo Mathew, Hoon Kim

المصدر: Pharmaceuticals; Volume 16; Issue 2; Pages: 147

مصطلحات موضوعية: KAND, KIF1A gene, microtubule, kinesin motor protein, neurological disorder

الوصف: KIF1A-associated neurological diseases (KANDs) are a group of inherited conditions caused by changes in the microtubule (MT) motor protein KIF1A as a result of KIF1A gene mutations. Anterograde transport of membrane organelles is facilitated by the kinesin family protein encoded by the MT-based motor gene KIF1A. Variations in the KIF1A gene, which primarily affect the motor domain, disrupt its ability to transport synaptic vesicles containing synaptophysin and synaptotagmin leading to various neurological pathologies such as hereditary sensory neuropathy, autosomal dominant and recessive forms of spastic paraplegia, and different neurological conditions. These mutations are frequently misdiagnosed because they result from spontaneous, non-inherited genomic alterations. Whole-exome sequencing (WES), a cutting-edge method, assists neurologists in diagnosing the illness and in planning and choosing the best course of action. These conditions are simple to be identified in pediatric and have a life expectancy of 5–7 years. There is presently no permanent treatment for these illnesses, and researchers have not yet discovered a medicine to treat them. Scientists have more hope in gene therapy since it can be used to cure diseases brought on by mutations. In this review article, we discussed some of the experimental gene therapy methods, including gene replacement, gene knockdown, symptomatic gene therapy, and cell suicide gene therapy. It also covered its clinical symptoms, pathogenesis, current diagnostics, therapy, and research advances currently occurring in the field of KAND-related disorders. This review also explained the impact that gene therapy can be designed in this direction and afford the remarkable benefits to the patients and society.

وصف الملف: application/pdf

العلاقة: Pharmaceutical Technology; https://dx.doi.org/10.3390/ph16020147Test

الإتاحة: https://doi.org/10.3390/ph16020147Test

المؤلفون: Rivera Alvarez, José, Asselin, Laure, Tilly, Peggy, Benoit, Roxane, Batisse, Claire, Richert, Ludovic, Batisse, Julien, Morlet, Bastien, Levet, Florian, Schwaller, Noémie, Mély, Yves, Ruff, M., Reymann, Anne-Cécile, Godin, Juliette

المساهمون: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Bioimagerie et Pathologies (LBP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Interdisciplinary Institute for Neuroscience Bordeaux (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Bordeaux Imaging Center (BIC), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-17-EURE-0023,IMCBio,Integrative Molecular and Cellular Biology(2017), ANR-20-SFRI-0012,STRAT'US,Façonner les talents en formation et en recherche à l'Université de Strasbourg(2020), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010), ANR-19-CE13-0005,DeCaNu,Nucleation d'actine sous controle dévelopmental chez C. elegans.(2019)

المصدر: ISSN: 2211-1247.

مصطلحات موضوعية: Kif21b, actin, cytoskeleton, glia-guided locomotion, kinesin, microtubule, neuronal polarization, nucleokinesis, radial migration, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis

الوصف: International audience ; Completion of neuronal migration is critical for brain development. Kif21b is a plus-end-directed kinesin motor protein that promotes intracellular transport and controls microtubule dynamics in neurons. Here we report a physiological function of Kif21b during radial migration of projection neurons in the mouse developing cortex. In vivo analysis in mouse and live imaging on cultured slices demonstrate that Kif21b regulates the radial glia-guided locomotion of newborn neurons independently of its motility on microtubules. We show that Kif21b directly binds and regulates the actin cytoskeleton both in vitro and in vivo in migratory neurons. We establish that Kif21b-mediated regulation of actin cytoskeleton dynamics influences branching and nucleokinesis during neuronal locomotion. Altogether, our results reveal atypical roles of Kif21b on the actin cytoskeleton during migration of cortical projection neurons.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/37418324; hal-04163589; https://hal.science/hal-04163589Test; https://hal.science/hal-04163589/documentTest; https://hal.science/hal-04163589/file/KIf21b-2023.pdfTest; PUBMED: 37418324

الإتاحة: https://doi.org/10.1016/j.celrep.2023.112744Test
https://hal.science/hal-04163589Test
https://hal.science/hal-04163589/documentTest
https://hal.science/hal-04163589/file/KIf21b-2023.pdfTest