scholarly journals Parts list for a microtubule depolymerising kinesin

2018 ◽  
Vol 46 (6) ◽  
pp. 1665-1672 ◽  
Author(s):  
Claire T. Friel ◽  
Julie P. Welburn
Keyword(s):  
Chromosome Segregation ◽  
Molecular Motors ◽  
Neuronal Development ◽  
Current Understanding ◽  
Cellular Functions ◽  
Microtubule Cytoskeleton ◽  
Microtubule Binding ◽  
Large Group ◽  
Kinesin Superfamily ◽  
Different Parts

The Kinesin superfamily is a large group of molecular motors that use the turnover of ATP to regulate their interaction with the microtubule cytoskeleton. The coupled relationship between nucleotide turnover and microtubule binding is harnessed in various ways by these motors allowing them to carry out a variety of cellular functions. The Kinesin-13 family is a group of specialist microtubule depolymerising motors. Members of this family use their microtubule destabilising activity to regulate processes such as chromosome segregation, maintenance of cilia and neuronal development. Here, we describe the current understanding of the structure of this family of kinesins and the role different parts of these proteins play in their microtubule depolymerisation activity and in the wider function of this family of kinesins.

scholarly journals Yeast Kinetochores Do Not Stabilize Stu2p-dependent Spindle Microtubule Dynamics

2003 ◽  
Vol 14 (10) ◽  
pp. 4181-4195 ◽  
Author(s):  
Chad G. Pearson ◽  
Paul S. Maddox ◽  
Ted R. Zarzar ◽  
E.D. Salmon ◽  
Kerry Bloom
Keyword(s):  
Chromosome Segregation ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Regulatory Mechanism ◽  
Metaphase Plate ◽  
Microtubule Dynamics ◽  
Spindle Microtubule ◽  
Microtubule Binding ◽  
Microtubule Stabilization ◽  
Kinetochore Function

The interaction of kinetochores with dynamic microtubules during mitosis is essential for proper centromere motility, congression to the metaphase plate, and subsequent anaphase chromosome segregation. Budding yeast has been critical in the discovery of proteins necessary for this interaction. However, the molecular mechanism for microtubule–kinetochore interactions remains poorly understood. Using live cell imaging and mutations affecting microtubule binding proteins and kinetochore function, we identify a regulatory mechanism for spindle microtubule dynamics involving Stu2p and the core kinetochore component, Ndc10p. Depleting cells of the microtubule binding protein Stu2p reduces kinetochore microtubule dynamics. Centromeres remain under tension but lack motility. Thus, normal microtubule dynamics are not required to maintain tension at the centromere. Loss of the kinetochore (ndc10-1, ndc10-2, and ctf13-30) does not drastically affect spindle microtubule turnover, indicating that Stu2p, not the kinetochore, is the foremost governor of microtubule dynamics. Disruption of kinetochore function with ndc10-1 does not affect the decrease in microtubule turnover in stu2 mutants, suggesting that the kinetochore is not required for microtubule stabilization. Remarkably, a partial kinetochore defect (ndc10-2) suppresses the decreased spindle microtubule turnover in the absence of Stu2p. These results indicate that Stu2p and Ndc10p differentially function in controlling kinetochore microtubule dynamics necessary for centromere movements.

scholarly journals The kinetoplastid kinetochore protein KKT4 is an unconventional microtubule tip–coupling protein

2018 ◽  
Vol 217 (11) ◽  
pp. 3886-3900 ◽  
Author(s):  
Aida Llauró ◽  
Hanako Hayashi ◽  
Megan E. Bailey ◽  
Alex Wilson ◽  
Patryk Ludzia ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Binding Activity ◽  
Significant Similarity ◽  
Load Bearing ◽  
Kinetochore Protein ◽  
Microtubule Binding ◽  
Binding Domains ◽  
Microtubule Binding Domain ◽  
Coupling Protein

Kinetochores are multiprotein machines that drive chromosome segregation by maintaining persistent, load-bearing linkages between chromosomes and dynamic microtubule tips. Kinetochores in commonly studied eukaryotes bind microtubules through widely conserved components like the Ndc80 complex. However, in evolutionarily divergent kinetoplastid species such as Trypanosoma brucei, which causes sleeping sickness, the kinetochores assemble from a unique set of proteins lacking homology to any known microtubule-binding domains. Here, we show that the T. brucei kinetochore protein KKT4 binds directly to microtubules and maintains load-bearing attachments to both growing and shortening microtubule tips. The protein localizes both to kinetochores and to spindle microtubules in vivo, and its depletion causes defects in chromosome segregation. We define a microtubule-binding domain within KKT4 and identify several charged residues important for its microtubule-binding activity. Thus, despite its lack of significant similarity to other known microtubule-binding proteins, KKT4 has key functions required for driving chromosome segregation. We propose that it represents a primary element of the kinetochore–microtubule interface in kinetoplastids.

scholarly journals Conserved mechanisms of microtubule-stimulated ADP release, ATP binding, and force generation in transport kinesins

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Joseph Atherton ◽  
Irene Farabella ◽  
I-Mei Yu ◽  
Steven S Rosenfeld ◽  
Anne Houdusse ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Conformational Changes ◽  
Catalytic Site ◽  
Fundamental Question ◽  
Force Generation ◽  
Atp Binding ◽  
Cellular Functions ◽  
Microtubule Binding ◽  
Cryo Electron Microscopy ◽  
Adp Release

Kinesins are a superfamily of microtubule-based ATP-powered motors, important for multiple, essential cellular functions. How microtubule binding stimulates their ATPase and controls force generation is not understood. To address this fundamental question, we visualized microtubule-bound kinesin-1 and kinesin-3 motor domains at multiple steps in their ATPase cycles—including their nucleotide-free states—at ∼7 Å resolution using cryo-electron microscopy. In both motors, microtubule binding promotes ordered conformations of conserved loops that stimulate ADP release, enhance microtubule affinity and prime the catalytic site for ATP binding. ATP binding causes only small shifts of these nucleotide-coordinating loops but induces large conformational changes elsewhere that allow force generation and neck linker docking towards the microtubule plus end. Family-specific differences across the kinesin–microtubule interface account for the distinctive properties of each motor. Our data thus provide evidence for a conserved ATP-driven mechanism for kinesins and reveal the critical mechanistic contribution of the microtubule interface.

scholarly journals The stoichiometry of the outer kinetochore is modulated by microtubule-proximal regulatory factors

2019 ◽  
Vol 218 (7) ◽  
pp. 2124-2135 ◽  
Author(s):  
Karthik Dhatchinamoorthy ◽  
Jay R. Unruh ◽  
Jeffrey J. Lange ◽  
Michaella Levy ◽  
Brian D. Slaughter ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Single Particle ◽  
Super Resolution ◽  
Molecular Machine ◽  
Cyclin Dependent Kinase ◽  
Centromeric Dna ◽  
Microtubule Binding ◽  
Regulatory Factors

The kinetochore is a large molecular machine that attaches chromosomes to microtubules and facilitates chromosome segregation. The kinetochore includes submodules that associate with the centromeric DNA and submodules that attach to microtubules. Additional copies of several submodules of the kinetochore are added during anaphase, including the microtubule binding module Ndc80. While the factors governing plasticity are not known, they could include regulation based on microtubule–kinetochore interactions. We report that Fin1 localizes to the microtubule-proximal edge of the kinetochore cluster during anaphase based on single-particle averaging of super-resolution images. Fin1 is required for the assembly of normal levels of Dam1 and Ndc80 submodules. Levels of Ndc80 further depend on the Dam1 microtubule binding complex. Our results suggest the stoichiometry of outer kinetochore submodules is strongly influenced by factors at the kinetochore–microtubule interface such as Fin1 and Dam1, and phosphorylation by cyclin-dependent kinase. Outer kinetochore stoichiometry is remarkably plastic and responsive to microtubule-proximal regulation.

scholarly journals Recruiting a microtubule-binding complex to DNA directs chromosome segregation in budding yeast

2009 ◽  
Vol 11 (9) ◽  
pp. 1116-1120 ◽  
Author(s):  
Soni Lacefield ◽  
Derek T. C. Lau ◽  
Andrew W. Murray
Keyword(s):  
Chromosome Segregation ◽  
Budding Yeast ◽  
Microtubule Binding

scholarly journals Run length distribution of dimerized kinesin-3 molecular motors: comparison with dimeric kinesin-1

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Si-Kao Guo ◽  
Xiao-Xuan Shi ◽  
Peng-Ye Wang ◽  
Ping Xie
Keyword(s):  
Molecular Motors ◽  
Average Run Length ◽  
Length Distribution ◽  
Dissociation Rate ◽  
Run Length ◽  
Proposed Model ◽  
Run Length Distribution ◽  
Run Lengths ◽  
Kinesin Superfamily ◽  
Single Exponential

AbstractKinesin-3 and kinesin-1 molecular motors are two families of the kinesin superfamily. It has been experimentally revealed that in monomeric state kinesin-3 is inactive in motility and cargo-mediated dimerization results in superprocessive motion, with an average run length being more than 10-fold longer than that of kinesin-1. In contrast to kinesin-1 showing normally single-exponential distribution of run lengths, dimerized kinesin-3 shows puzzlingly Gaussian distribution of run lengths. Here, based on our proposed model, we studied computationally the dynamics of kinesin-3 and compared with that of kinesin-1, explaining quantitatively the available experimental data and revealing the origin of superprocessivity and Gaussian run length distribution of kinesin-3. Moreover, predicted results are provided on ATP-concentration dependence of run length distribution and force dependence of mean run length and dissociation rate of kinesin-3.

Dividing the goods: co-ordination of chromosome biorientation and mitotic checkpoint signalling by mitotic kinases

2009 ◽  
Vol 37 (5) ◽  
pp. 971-975 ◽  
Author(s):  
Geert J.P.L. Kops
Keyword(s):  
Cell Division ◽  
Chromosome Segregation ◽  
Short Review ◽  
Mitotic Checkpoint ◽  
Current Understanding ◽  
Chromosomal Stability ◽  
Mitotic Kinases

Error-free chromosome segregation during cell division relies on chromosome biorientation and mitotic checkpoint activity. A group of unrelated kinases controls various aspects of both processes. The present short review outlines our current understanding of the roles of these kinases in maintaining chromosomal stability.

scholarly journals Insights into the mechanisms of myosin and kinesin molecular motors from the single-molecule unbinding force measurements

2010 ◽  
Vol 7 (suppl_3) ◽  
Author(s):  
Sergey V. Mikhailenko ◽  
Yusuke Oguchi ◽  
Shin'ichi Ishiwata
Keyword(s):  
Single Molecule ◽  
Molecular Motors ◽  
Atp Hydrolysis ◽  
Force Measurements ◽  
Cellular Functions ◽  
Mechanochemical Cycle ◽  
The Individual ◽  
Experimental Geometry ◽  
External Loads ◽  
Individual Motor

In cells, ATP (adenosine triphosphate)-driven motor proteins, both cytoskeletal and nucleic acid-based, operate on their corresponding ‘tracks’, that is, actin, microtubules or nucleic acids, by converting the chemical energy of ATP hydrolysis into mechanical work. During each mechanochemical cycle, a motor proceeds via several nucleotide states, characterized by different affinities for the ‘track’ filament and different nucleotide (ATP or ADP) binding kinetics, which is crucial for a motor to efficiently perform its cellular functions. The measurements of the rupture force between the motor and the track by applying external loads to the individual motor–substrate bonds in various nucleotide states have proved to be an important tool to obtain valuable insights into the mechanism of the motors' performance. We review the application of this technique to various linear molecular motors, both processive and non-processive, giving special attention to the importance of the experimental geometry.

scholarly journals A critical role for Apc in hematopoietic stem and progenitor cell survival

2008 ◽  
Vol 205 (9) ◽  
pp. 2163-2175 ◽  
Author(s):  
Zhijian Qian ◽  
Lina Chen ◽  
Anthony A. Fernald ◽  
Bart O. Williams ◽  
Michelle M. Le Beau
Keyword(s):  
Chromosome Segregation ◽  
Bone Marrow Failure ◽  
Critical Role ◽  
Cellular Functions ◽  
Erythroid Progenitor ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor ◽  
Cell Cycle Entry ◽  
Genes Encoding

The adenomatous polyposis coli (Apc) tumor suppressor is involved in the initiation and progression of colorectal cancer via regulation of the Wnt signaling cascade. In addition, Apc plays an important role in multiple cellular functions, including cell migration and adhesion, spindle assembly, and chromosome segregation. However, its role during adult hematopoiesis is unknown. We show that conditional inactivation of Apc in vivo dramatically increases apoptosis and enhances cell cycle entry of hematopoietic stem cells (HSCs)/ hematopoietic progenitor cells (HPCs), leading to their rapid disappearance and bone marrow failure. The defect in HSCs/HPCs caused by Apc ablation is cell autonomous. In addition, we found that loss of Apc leads to exhaustion of the myeloid progenitor pool (common myeloid progenitor, granulocyte-monocyte progenitor, and megakaryocyte-erythroid progenitor), as well as the lymphoid-primed multipotent progenitor pool. Down-regulation of the genes encoding Cdkn1a, Cdkn1b, and Mcl1 occurs after acute Apc excision in candidate HSC populations. Together, our data demonstrate that Apc is essential for HSC and HPC maintenance and survival.

scholarly journals Whole-proteome genetic analysis of dependencies in assembly of a vertebrate kinetochore

2015 ◽  
Vol 211 (6) ◽  
pp. 1141-1156 ◽  
Author(s):  
Itaru Samejima ◽  
Christos Spanos ◽  
Flavia de Lima Alves ◽  
Tetsuya Hori ◽  
Marinela Perpelescu ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Mitotic Chromosome ◽  
Protein Complexes ◽  
Interacting Proteins ◽  
Quantitative Mass Spectrometry ◽  
Mitotic Chromosomes ◽  
Microtubule Binding ◽  
Checkpoint Signaling ◽  
Ndc80 Complex ◽  
Stable Association

Kinetochores orchestrate mitotic chromosome segregation. Here, we use quantitative mass spectrometry of mitotic chromosomes isolated from a comprehensive set of chicken DT40 mutants to examine the dependencies of 93 confirmed and putative kinetochore proteins for stable association with chromosomes. Clustering and network analysis reveal both known and unexpected aspects of coordinated behavior for members of kinetochore protein complexes. Surprisingly, CENP-T depends on CENP-N for chromosome localization. The Ndc80 complex exhibits robust correlations with all other complexes in a “core” kinetochore network. Ndc80 associated with CENP-T interacts with a cohort of Rod, zw10, and zwilch (RZZ)–interacting proteins that includes Spindly, Mad1, and CENP-E. This complex may coordinate microtubule binding with checkpoint signaling. Ndc80 associated with CENP-C forms the KMN (Knl1, Mis12, Ndc80) network and may be the microtubule-binding “workhorse” of the kinetochore. Our data also suggest that CENP-O and CENP-R may regulate the size of the inner kinetochore without influencing the assembly of the outer kinetochore.

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