Intraflagellar transport: mechanisms of motor action, cooperation, and cargo delivery

Prevo, Bram; Scholey, Jonathan M.; Peterman, Erwin J. G.

doi:10.1111/febs.14068

Cited by 186 publications

(212 citation statements)

References 242 publications

(457 reference statements)

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“…Yet unlike kinesin-1, this kinesin was heterotrimeric with two different motor polypeptides and a non-motor accessory protein designated kinesin associated polypeptide (KAP). Soon thereafter, heterodimeric and heterotrimeric kinesins were identified in multiple eukaryotic species and like kinesin-1, they were associated with long distance cargo transport (reviewed in (3)(4)(5)(6)(7)11)). …”

Section: Kinesin-2 Subfamilymentioning

confidence: 99%

“…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)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)). Kinesins are classified into 15 different subfamilies, yet they share a structurally conserved kinesin motor domain (1,3,(13)(14)(15)(16).…”

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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: Kinesin-2 Subfamilymentioning

confidence: 99%

mentioning

confidence: 99%

Kinesin-2 motors: Kinetics and biophysics

Gilbert

Guzik-Lendrum

Rayment

2018

Journal of Biological Chemistry

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“…Intraflagellar transport (IFT) is the process operating between the ciliary/flagellar membrane and the microtubular axoneme of motile and primary cilia (Ishikawa and Marshall, 2017; Mourao et al, 2016; Prevo et al, 2017). IFT particles, composed of complexes A and B, carry flagellar cargo proteins to their assembly site at the flagellar tip by driven by kinesin (Scholey, 2013), and turnover products from the tip back to the cytoplasm by cytoplasmic dynein (Hou and Witman, 2015).…”

Section: Introductionmentioning

confidence: 99%

Intraflagellar transporter protein (IFT27), an IFT25 binding partner, is essential for male fertility and spermiogenesis in mice

Zhang

Liu

et al. 2017

Developmental Biology

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Intraflagellar transport (IFT) is an evolutionarily conserved mechanism essential for the assembly and maintenance of most eukaryotic cilia and flagella. In mice, mutations in IFT proteins have been shown to cause several ciliopathies including retinal degeneration, polycystic kidney disease, and hearing loss. However, little is known about its role in the formation of the sperm tail, which has the longest flagella of mammalian cells. IFT27 is a component of IFT-B complex and binds to IFT25 directly. In mice, IFT27 is highly expressed in the testis. To investigate the role of IFT27 in male germ cells, the floxed Ift27 mice were bred with Stra8-iCre mice so that the Ift27 gene was disrupted in spermatocytes/spermatids. The Ift27:Stra8-iCre mutant mice did not show any gross abnormalities, and all of the mutant mice survive to adulthood. There was no difference between testis weight/body weight between controls and mutant mice. All adult homozygous mutant males examined were completely infertile. Histological examination of the testes revealed abnormally developed germ cells during the spermiogenesis phase. The epididymis contained round bodies of cytoplasm. Sperm number was significantly reduced compared to the controls and only about 2% of them remained significantly reduced motility. Examination of epididymal sperm by light microscopy and SEM revealed multiple morphological abnormalities including round heads, short and bent tails, abnormal thickness of sperm tails in some areas, and swollen tail tips in some sperm. TEM examination of epididymal sperm showed that most sperm lost the “9+2” axoneme structure, and the mitochondria sheath, fibrous sheath, and outer dense fibers were also disorganized. Some sperm flagella also lost cell membrane. Levels of IFT25 and IFT81 were significantly reduced in the testis of the conditional Ift27 knockout mice, and levels of IFT20, IFT74, and IFT140 were not changed. Sperm lipid rafts, which were disrupted in the conditional Ift25 knockout mice, appeared to be normal in the conditional Ift27 knockout mice. Our findings suggest that like IFT25, IFT27, even though not required to ciliogenesis in somatic cells, is essential for sperm flagella formation, sperm function, and male fertility in mice. IFT25 and IFT27 control sperm formation/function through many common mechanisms, but IFT25 has additional roles beyond IFT27.

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“…The assembly and maintenance of cilia/flagella are mediated by a motor-driven trafficking system termed intraflagellar transport (IFT), which was first described in the green algae Chlamydomonas reinhardtii (Ishikawa and Marshall 2011; Kozminski et al 1993). IFT is characterized by a bidirectional movement of large protein complexes called IFT particles along the axoneme of cilia/flagella and functions independently of ciliary/flagellar beat (Kozminski et al 1993; Prevo et al 2017). IFT machinery is essential for the movement of IFT particles including ciliary/flagellar precursors and signaling molecules from the basal body to the site of assembly at the axonemal tip of cilia/flagella with the aid of kinesin-2 motors (anterograde trafficking) (Cole et al 1998; Huet et al 2014; Pedersen et al 2006; Scholey 2013).…”

Section: Introductionmentioning

confidence: 99%

“…The complex IFT-A contains 6 subunits while the complex IFT-B comprises 16 subunits. Many of these IFT proteins harbor typical protein-protein interaction domains including coiled-coil motifs, tetratricopeptide repeats (TPRs) or tryptophan/aspartic acid repeats (WD40 repeats) (Cole et al 1998; Piperno and Mead 1997; Prevo et al 2017). Mutations disrupting IFT subunits usually result in short or completely absent cilia/flagella, or formation of flagellar bulges due to defects in anterograde and/or retrograde transport (Absalon et al 2008; Iomini et al 2009; Tsao and Gorovsky 2008).…”

Section: Introductionmentioning

confidence: 99%

Intraflagellar transporter protein 140 (IFT140), a component of IFT‐A complex, is essential for male fertility and spermiogenesis in mice

Zhang

Liu

et al. 2018

Cytoskeleton

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Intraflagellar transport (IFT) is a conserved mechanism essential for the assembly and maintenance of most eukaryotic cilia and flagella. However, little is known about its role in sperm flagella formation and male fertility. IFT140 is a component of IFT-A complex. In mouse, it is highly expressed in the testis. Ift140 gene was inactivated specifically in mouse spermatocytes/spermatids. The mutant mice did not show any gross abnormalities, but all were infertile and associated with significantly reduced sperm number and motility. Multiple sperm morphological abnormalities were discovered, including amorphous heads, short/bent flagella and swollen tail tips, as well as vesicles along the flagella due to spermiogenesis defects. The epididymides contained round bodies of cytoplasm derived from the sloughing of the cytoplasmic lobes and residual bodies. Knockout of Ift140 did not significantly affect testicular expression levels of selective IFT components but localization of IFT27 and IFT88, two components of IFT-B complex, was changed. Our findings demonstrate that IFT140 is a key regulator for male fertility and normal spermiogenesis in mice. It not only plays a role in sperm flagella assembling, but is also involved in critical assembly of proteins that interface between the germ cell plasma and the Sertoli cell.

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Intraflagellar transport: mechanisms of motor action, cooperation, and cargo delivery

Cited by 186 publications

References 242 publications

Kinesin-2 motors: Kinetics and biophysics

Kinesin-2 motors: Kinetics and biophysics

Intraflagellar transporter protein (IFT27), an IFT25 binding partner, is essential for male fertility and spermiogenesis in mice

Intraflagellar transporter protein 140 (IFT140), a component of IFT‐A complex, is essential for male fertility and spermiogenesis in mice

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