Family-specific Kinesin Structures Reveal Neck-linker Length Based on Initiation of the Coiled-coil

Phillips, R.K.; Peter, Logan G.; Gilbert, Susan P.; Rayment, Ivan

doi:10.1074/jbc.m116.737577

Cited by 17 publications

(16 citation statements)

References 91 publications

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“…Moreover, this study reinforced the importance of conjoining the native sequences of both the native neck linker and helix a7 for engineered constructs to study the motile properties of kinesin family members (80). In addition, the Phillips et al structural study revealed similar disparities in the coiled-coil predictions for a wide variety of non-motor proteins in the Protein Data Bank (80).…”

Section: Structural Studies Show That the Coiled-coil Predictions Wermentioning

confidence: 77%

“…Therefore, the neck linker is shortened from 17 residues to 12 residues, thus shorter than the neck linker of kinesin-1 at 14 residues. The crystal structures of both Eg5 and CENP-E reveal much shorter neck linkers than predicted (80). Helix a7 of Eg5 begins at Lys-371 instead of Ile-375, thus shortening the neck linker from the predicted 18 residues to 14 residues.…”

Section: Structural Studies Show That the Coiled-coil Predictions Wermentioning

confidence: 99%

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Kinesin-2 motors: Kinetics and biophysics

Gilbert

Guzik-Lendrum

Rayment

2018

Journal of Biological Chemistry

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Kinesin-2s are major transporters of cellular cargoes. This subfamily contains both homodimeric kinesins whose catalytic domains result from the same gene product and heterodimeric kinesins with motor domains derived from two different gene products. In this review, we focus on the progress to define the biochemical and biophysical properties of the kinesin-2 family members. Our understanding of their mechanochemical capabilities has been advanced by the ability to identify the kinesin-2 genes in multiple species, expression and purification of these motors for single molecule and ensemble assays, and development of new technologies enabling quantitative measurements of kinesin activity with greater sensitivity.Kinesins constitute a superfamily of microtubule-based molecular motor enzymes that couple the chemical energy from ATP turnover to force production for diverse cellular functions (reviewed in (1-12)). Kinesins are classified into 15 different subfamilies, yet they share a structurally conserved kinesin motor domain (1,3,(13)(14)(15)(16). However, key amino acid residue changes can confer unique mechanochemical properties to each kinesin, which in turn specify cellular function. The N-terminal kinesins are composed of an N-terminal motor domain connected to a long a-helical region that dimerizes into a coiled-coil stalk that ends with a C-terminal domain that may interact with specific adaptor proteins for cargo linkage (Fig. 1). N-kinesin subfamilies include conventional kinesin-1, kinesin-2, kinesin-3, kinesin-5 Eg5/KSP, and kinesin-7 CENP-E, and all are best known for their roles in intracellular transport.N-kinesins carry cargo directionally toward the plus-end of microtubules, which are polymerized from ab-tubulin subunits to form a cylindrical polymer of 13 protofilaments. The kinesins are able to "read" the polarity of the microtubule because of the structural asymmetry of ab-tubulin subunits. The movement of N-kinesins is designated as "processive," which implies that upon microtubule collision, a single, dimeric kinesin steps continuously toward the microtubule plus end in an asymmetric hand-over-hand manner hydrolyzing one ATP per 8-nm step for hundreds of steps (17)(18)(19)(20)(21)(22). The 8-nm step size results from the distance between adjacent ab-tubulin dimers along the microtubule lattice. As Fig. 2 illustrates, a processive kinesin binds the microtubule and then goes through a series of structural transitions, each modulated by nucleotide state. To maintain a processive run with continuous stepping, the Kinesin-2 Molecular Motors 2ATPase cycle of each head remains out-of-phase with the other to avoid premature release if both heads exist in a microtubule weak binding state simultaneously. The degree of processivity, quantified by "run length," varies between kinesin subfamilies and is regulated by a series of "gating" mechanisms in which a chemical and/or mechanical requirement must be satisfied to proceed forward. There has been significant effort to define the determinants of ...

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Section: Structural Studies Show That the Coiled-coil Predictions Wermentioning

confidence: 77%

Section: Structural Studies Show That the Coiled-coil Predictions Wermentioning

confidence: 99%

Kinesin-2 motors: Kinetics and biophysics

Gilbert

Guzik-Lendrum

Rayment

2018

Journal of Biological Chemistry

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“…( C ) The three‐dimensional structure of hCENP‐E's Neck‐linker and alpha 7 helix (PDB No. 5JVP) [Phillips et al., ]. ( D ) The molecular kinetics of CENP‐E on microtubules.…”

Section: The Structural Domains and Functional Motifs Of Kinesin‐7 Cementioning

confidence: 99%

Mechanisms of kinesin‐7 CENP‐E in kinetochore–microtubule capture and chromosome alignment during cell division

Zhong

Xiao

et al. 2019

Biology of the Cell

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Chromosome congression is essential for faithful chromosome segregation and genomic stability in cell division. Centromere-associated protein E (CENP-E), a plus-end-directed kinesin motor, is required for congression of poleproximal chromosomes in metaphase. CENP-E accumulates at the outer plate of kinetochores and mediates the kinetochore-microtubule capture. CENP-E also transports the chromosomes along spindle microtubules towards the equatorial plate. CENP-E interacts with Bub1-related kinase, Aurora B and core kinetochore components during kinetochore-microtubule attachment. In this review, we introduce the structures and mechanochemistry of kinesin-7 CENP-E. We highlight the complicated interactions between CENP-E and partner proteins during chromosome congression. We summarise the detailed roles and mechanisms of CENP-E in mitosis and meiosis, including the kinetochore-microtubule capture, chromosome congression/alignment in metaphase and the regulation of spindle assembly checkpoint. We also shed a light on the roles of CENP-E in tumourigenesis and CENP-E's specific inhibitors.

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“…Additional evidence in support of this hypothesis is that the sequence of the neck linker followed by helix ␣7 for KIF3B and KIF3C are identical with the exception of a single residue. Furthermore, the structures of the neck linkers and ␣7 for KIF3A and KIF3C, and hence KIF3B, are very similar (71). Thus, it is likely that the modulation arises from interactions between the motor domains themselves that cannot be achieved by the homodimers despite how catalytically similar KIF3AA and KIF3BB are.…”

Section: Discussionmentioning

confidence: 95%

Heterodimerization of Kinesin-2 KIF3AB Modulates Entry into the Processive Run

Albracht

Guzik-Lendrum

Rayment

et al. 2016

Journal of Biological Chemistry

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Mammalian KIF3AB is an N-terminal processive kinesin-2 that is best known for its roles in intracellular transport. There has been significant interest in KIF3AB to define the key principles that underlie its processivity but also to define the mechanistic basis of its sensitivity to force. In this study, the kinetics for entry into the processive run were quantified. The results show for KIF3AB that the kinetics of microtubule association at 7 M ؊1 s ؊1 is less than the rates observed for KIF3AA at 13 M ؊1 s ؊1 or KIF3BB at 11.9 M ؊1 s ؊1 . ADP release after microtubule association for KIF3AB is 33 s ؊1 and is significantly slower than ADP release from homodimeric KIF3AA and KIF3BB, which reach 80 -90 s ؊1 . To explore the interhead communication implied by the rate differences at these first steps, we compared the kinetics of KIF3AB microtubule association followed by ADP release with the kinetics for mixtures of KIF3AA plus KIF3BB. Surprisingly, the kinetics of KIF3AB are not equivalent to any of the mixtures of KIF3AA ؉ KIF3BB. In fact, the transients for each of the mixtures overlay the transients for KIF3AA and KIF3BB. These results reveal that intermolecular communication within the KIF3AB heterodimer modulates entry into the processive run, and the results suggest that it is the high rate of microtubule association that drives rebinding to the microtubule after force-dependent motor detachment.The kinesin-2 subfamily members are ubiquitously expressed and act as major transporters of intracellular cargoes (for reviews, see Refs. 1-5). In mammals, KIF3A, KIF3B, and KAP 4 expression yields a heterotrimeric complex (6 -9). The motor polypeptides KIF3A and KIF3B form a heterodimeric motor, KIF3AB, and the nonmotor polypeptide KAP associates at the C terminus of KIF3AB. KAP is a distinctive adaptor protein in that it is largely composed of armadillo repeats (10, 11), and it is these motifs that provide the specificity of interaction between KIF3AB and KAP and between KIF3AB-KAP and its specific cargo. A heterotrimeric kinesin-2 complex with KAP has been described in many species since its discovery in sea urchin eggs including Mus musculus, Chlamydomonas, Caenorhabditis elegans, Drosophila, Xenopus,[12][13][14][15][16][17][18][19].KIF3A, KIF3B, and KAP are essential genes (20 -25). Knockout mice for KIF3A or KIF3B have revealed the absence of cilia and a randomized left-right body axis (20 -22). These nodal cilia are crucial for the proper mesodermal patterning during embryogenesis to establish the left-right body asymmetry. Other studies have linked KIF3AB-KAP to cilia-dependent signal transduction cascades including the Hedgehog signaling pathway (26,27). The role of intraflagellar transport in ciliogenesis is considered the basis for KIF3AB-KAP to be an essential protein for development. KIF3AB-KAP is also implicated in a variety of cytoplasmic transport events including organelles, melanosomes, mRNA granules, and membrane-bound vesicles (2, 4, 25, 28 -30). KIF3AB-KAP is also essential for axon elongation...

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Family-specific Kinesin Structures Reveal Neck-linker Length Based on Initiation of the Coiled-coil

Cited by 17 publications

References 91 publications

Kinesin-2 motors: Kinetics and biophysics

Kinesin-2 motors: Kinetics and biophysics

Mechanisms of kinesin‐7 CENP‐E in kinetochore–microtubule capture and chromosome alignment during cell division

Heterodimerization of Kinesin-2 KIF3AB Modulates Entry into the Processive Run

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