Kinesin-1 Discovery

Until the mid-1980’s, motor proteins that worked in concert with cytoplasmic microtubules represented a class of molecules whose identification remained a mystery. The existence of microtubule motors had been inferred from analysis of chromosome segregation and spindle dynamics during mitosis and meiosis, and of transport through the cytoplasm of membrane-bounded organelles. Numerous studies indicated that these motile phenomena required both microtubules and ATP, suggesting that mechanochemical ATPases were responsible for moving a variety of intracellular cargo along cytoplasmic microtubules. For many years the leading candidate ATPase was dynein, which had been known since the 1960’s to be a motor for ciliary and flagellar motility [1]. Periodic reports of cytoplasmic dyneins emerged over the ensuing years, but the first definitive evidence that such proteins existed was not published until 1987 [2, 3]. The discovery of cytoplasmic dynein represented a landmark in cell biology, but occured two years after publication of an equally momentous event, the discovery of the novel microtubule motor protein, Kinesin-1 (formerly known as kinesin, conventional kinesin or KHC) [4-6].

The discovery of Kinesin-1 stemmed directly from real-time observation of fast axonal transport in isolated squid axoplasm by video-enhanced light microscopy. The non-hydrolyzable ATP analog, AMP-PNP, was found to inhibit fast axonal transport and to promote tight binding of organelles to microtubules. This key observation suggested that AMP-PNP induces the formation of rigor complexes consisting of organelles, microtubules and microtubule motor proteins [7].

To identify the putative motor, taxol-stabilized microtubules were isolated from squid optic lobes or vertebrate brain in the presence or absence of AMP-PNP. Analysis of the microtubules by SDS-PAGE revealed an ~120 kDa polypeptide that bound to microtubules in an AMP-PNP-dependent manner. The ATPase activity of the AMP-PNP microtubules was much higher than that of the control microtubules [4]. Moreover, a multisubunit enzyme containing the ~120 kDa polypeptide was purified and when adsorbed to glass coverslips, promoted ATP-dependent gliding of microtubules. Based on its mechanochemical activity, the ability to induce ATP-dependent microtubule gliding, the protein was aptly named kinesin (recently renamed Kinesin-1) [5,8].

Further studies have led to the discovery of a large number of proteins that are related in structure to Kinesin-1 and constititute the kinesin superfamily of motor proteins. These proteins are found in organisms representing all of the major eukaryotic kingdoms. The common bond among the kinesins is a highly conserved ‘motor’ domain, ~350 amino acids long, which contains binding sites for ATP and microtubules. The kinesin proteins are presumed to function in vivo as motors for microtubule-dependent motile phenomena, such as membrane transport and chromosome movement during meiosis and mitosis.

Contributed by George S. Bloom

Literature Cited

1. Gibbons, IR. 1965. Chemical dissection of cilia. Arch. Biol. (Liege) 76: 317-352.
2. Paschal, BM, Shpetner, HS and Vallee, RB. 1987. MAP 1C is a microtubule-activated ATPase which translocates microtubules in vitro and has dynein-like properties. J. Cell Biol. 105: 1273-1282.
3. Lye, RJ, Porter, ME, Scholey, JM and McIntosh, JR. 1987. Identification of a microtubule-based cytoplasmic motor in the nematode C. elegans. Cell 51: 309-318.
4. Brady, ST. 1985. A novel brain ATPase with properties expected for the fast axonal transport motor. Nature 317: 73-75.
5. Vale, RD, Reese, TS and Sheetz, MP. 1985. Identification of a novel force-generating protein, kinesin, involved in microtubule-based motility. Cell 42: 39-50.
6. Scholey, JM, Porter, ME, Grissom, PM and McIntosh, JR. 1985. Identification of kinesin in sea urchin eggs, and evidence for its localization in the mitotic spindle. Nature 318: 483-486.
7. Lasek, RJ and Brady, ST. 1985. Attachment of transported vesicles to microtubules in axoplasm is facilitated by AMP-PNP. Nature 316: 645-647.
8. Lawrence, CJ, et al. 2004. A standardized kinesin nomenclature. J. Cell Biol. 167: 19-22.

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