Kinesin-2 KIF3AC and KIF3AB Can Drive Long-Range Transport along Microtubules

Guzik-Lendrum, Stephanie; Rank, Katherine C.; Bensel, Brandon M.; Taylor, Keenan C.; Rayment, Ivan; Gilbert, Susan P.

doi:10.1016/j.bpj.2015.08.004

Cited by 30 publications

(110 citation statements)

References 69 publications

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“…Intermolecular Communication Modulates KIF3AC Entry into Processive Run-Our single molecule motility analysis (30) revealed that KIF3AC is more processive than KIF3AA or KIF3CC based on the run length data, implying that processivity is tuned in part by the intermolecular communication that occurs within the heterodimer. In addition, the results for MT association coupled with ADP release indicate a role for head-head communication because the behavior of KIF3AC is not equivalent to either KIF3AA or KIF3CC.…”

Section: Resultsmentioning

confidence: 91%

“…The results for KIF3AA in comparison with KIF3CC were striking because despite sequence similarity between KIF3A and KIF3C, KIF3AA was a very fast and processive kinesin, yet KIF3CC, although processive, was exceedingly slow (Table 1). In contrast, the properties of KIF3AA and KIF3BB were more similar to each other (30,31). This obvious disparity between KIF3AA and KIF3CC raises the question of what is the contribution of each motor head for KIF3AC function.…”

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confidence: 92%

“…The plasmid for KIF3CC homodimer expression is the same as for heterodimer expression. The resulting constructs were sequence-verified over the entire ORF insert (30).…”

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confidence: 99%

“…KIF3 Protein Expression and Purification-KIF3 motors were expressed in Escherichia coli BL21-CodonPlus (DE3)-RIL cell line (Stratagene, La Jolla, CA) for purification as described in detail previously (30,32). To achieve the purification of KIF3AC heterodimers, sequential affinity columns were used.…”

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confidence: 99%

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Fast or Slow, Either Head Can Start the Processive Run of Kinesin-2 KIF3AC

Zhang

Rayment

Gilbert

2016

Journal of Biological Chemistry

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Mammalian KIF3AC contains two distinct motor polypeptides and is best known for its role in organelle transport in neurons. Our recent studies showed that KIF3AC is as processive as conventional kinesin-1, suggesting that their ATPase mechanochemistry may be similar. However, the presence of two different motor polypeptides in KIF3AC implies that there must be a cellular advantage for the KIF3AC heterodimer. The hypothesis tested was whether there is an intrinsic bias within KIF3AC such that either KIF3A or KIF3C initiates the processive run. To pursue these experiments, a mechanistic approach was used to compare the pre-steady-state kinetics of KIF3AC to the kinetics of homodimeric KIF3AA and KIF3CC. Kinesin-2 subfamily members are best known for their roles in long distance cargo transport, but unlike other processive kinesins, the kinesin-2 subfamily includes both homodimeric and heterodimeric kinesins (reviewed in Refs. 1-3). In mammals, there are four kinesin-2 subfamily genes: KIF3A, KIF3B, KIF3C,. When expressed, KIF17 forms homodimers, yet KIF3A associates with either KIF3B or KIF3C to form the heterodimers KIF3AB and KIF3AC. In each case, these kinesin-2 molecular motors associate with nonmotor adaptor proteins to link the kinesin to its specific cargo (6, 15, 18 -27). Of the kinesin-2 adaptors, the kinesin-associated protein KAP with KIF3AB has resulted in the designation of KIF3AB-KAP as a heterotrimeric kinesin (6, 18 -22, 26). KIF3AB and KIF17 have been widely studied in multiple model organisms including Caenorhabditis elegans, Drosophila melanogaster, Danio rerio, as well as Mus musculus to understand their roles in intraflagellar transport and organelle transport for many other cellular functions (1-3). In contrast, KIF3AC has not been as well studied because there is not a true KIF3C ortholog in many of these model organisms. KIF3C exhibits a signature motif conserved in mammalian species, a 25-residue insert in loop L11 of the catalytic motor domain, which is enriched in glycines and serines (7, 28 -30). This L11 insert is not present in other kinesins. Furthermore, even though KIF3AB and KIF3AC share similarities in protein sequence and structure, KIF3AC appears to function specifically in neurons rather than ubiquitously as do KIF3AB and KIF17 (1, 2, 28).Recent single molecule studies revealed that heterodimers of KIF3AC and KIF3AB were as processive as kinesin-1 K560 based on their run lengths, indicating that KIF3AC and KIF3AB have the capacity for long distance intracellular transport (30). Furthermore, to begin to tease apart the contributions of each motor head, homodimers of KIF3AA, KIF3BB, and KIF3CC were generated and characterized. The results for KIF3AA in comparison with KIF3CC were striking because despite sequence similarity between KIF3A and KIF3C, KIF3AA was a very fast and processive kinesin, yet KIF3CC, although processive, was exceedingly slow (Table 1). In contrast, the properties of KIF3AA and KIF3BB were more similar to each other (30,31). This obvious disparity between...

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Section: Resultsmentioning

confidence: 91%

mentioning

confidence: 92%

“…The plasmid for KIF3CC homodimer expression is the same as for heterodimer expression. The resulting constructs were sequence-verified over the entire ORF insert (30).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Fast or Slow, Either Head Can Start the Processive Run of Kinesin-2 KIF3AC

Zhang

Rayment

Gilbert

2016

Journal of Biological Chemistry

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“…KIF3AC in particular has been implicated in neuronal repair (11). Both KIF3AB and KIF3AC are highly processive motors (46). Yet their neck-linker is predicted to be three residues longer than conventional kinesin, which would suggest that these motors should not be so processive (36).…”

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confidence: 99%

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

Phillips

Peter

Gilbert

et al. 2016

Journal of Biological Chemistry

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and -7 generate processive hand-over-hand 8-nm steps to transport intracellular cargoes toward the microtubule plus end. This processive motility requires gating mechanisms to coordinate the mechanochemical cycles of the two motor heads to sustain the processive run. A key structural element believed to regulate the degree of processivity is the necklinker, a short peptide of 12-18 residues, which connects the motor domain to its coiled-coil stalk. Although a shorter necklinker has been correlated with longer run lengths, the structural data to support this hypothesis have been lacking. To test this hypothesis, seven kinesin structures were determined by x-ray crystallography. Each included the neck-linker motif, followed by helix ␣7 that constitutes the start of the coiled-coil stalk. In the majority of the structures, the neck-linker length differed from predictions because helix ␣7, which initiates the coiled-coil, started earlier in the sequence than predicted. A further examination of structures in the Protein Data Bank reveals that there is a great disparity between the predicted and observed starting residues. This suggests that an accurate prediction of the start of a coiled-coil is currently difficult to achieve. These results are significant because they now exclude simple comparisons between members of the kinesin superfamily and add a further layer of complexity when interpreting the results of mutagenesis or protein fusion. They also re-emphasize the need to consider factors beyond the kinesin neck-linker motif when attempting to understand how inter-head communication is tuned to achieve the degree of processivity required for cellular function.

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Neuronal Intrinsic Regenerative Capacity: The Impact of Microtubule Organization and Axonal Transport

Murillo

Sousa

2018

Developmental Neurobiology

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In the adult vertebrate central nervous system, axons generally fail to regenerate. In contrast, peripheral nervous system axons are able to form a growth cone and regenerate upon lesion. Among the multiple intrinsic mechanisms leading to the formation of a new growth cone and to successful axon regrowth, cytoskeleton organization and dynamics is central. Here we discuss how multiple pathways that define the regenerative capacity converge into the regulation of the axonal microtubule cytoskeleton and transport. We further explore the use of dorsal root ganglion neurons as a model to study the neuronal regenerative ability. Finally, we address some of the unanswered questions in the field, including the mechanisms by which axonal transport might be modulated by injury, and the relationship between microtubule organization, dynamics, and axonal transport. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 00: 000-000, 2018.

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Kinesin-2 KIF3AC and KIF3AB Can Drive Long-Range Transport along Microtubules

Cited by 30 publications

References 69 publications

Fast or Slow, Either Head Can Start the Processive Run of Kinesin-2 KIF3AC

Fast or Slow, Either Head Can Start the Processive Run of Kinesin-2 KIF3AC

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

Neuronal Intrinsic Regenerative Capacity: The Impact of Microtubule Organization and Axonal Transport

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