The role of the neck linker and neck in kinesin velocity regulation

Kalchishkova, Nikolina GND

Kinesins are microtubule-associated motor proteins that convert the chemical energy of ATP into mechanical energy to perform a wide range of intracellular motility functions. Kinesin molecules represent long-stretched structures revealing distinct globular motor domains, composed of a conserved catalytic core and a so-called mechanical element. The catalytic core contains the microtubule- and ATP-binding sites. The mechanical element, comprising the neck linker and the neck, has been known to be crucial for motility generation, in general. Human neuron-specific kinesin-1 (KIF5A) and human mitotic kinesin-5 (Eg5) are kinesins with conserved motor domains, revealing about 40% identity in amino acid sequence. In addition, there is a very high level of similarity in their crystal structures. Regardless, Eg5 moves about 25 times slower than kinesin-1. Yet, the molecular mechanisms involved in velocity regulation of kinesin motors have been unclear. The central goal of this study was to find out which structural elements of the kinesin motor domain are responsible for motility generation, in general and for velocity regulation, in particular. With this intention, C-terminally truncated KIF5A and Eg5 proteins, lacking defined structural elements of the motor domain, were expressed and comparatively analyzed to define the minimal structural organization of the catalytic core required to generate activity. Furthermore, a series of KIF5A and Eg5 chimeras with interchanged neck linker and neck sequences were constructed to determine the structural elements involved in kinesin velocity regulation. The present study provides first evidence that the neck linker and neck elements are involved in the fine-tuning of the velocity at which kinesin motors move. Evolutionary the neck linker and neck might have evolved to adapt the variety of cellular motors to different biological functions.

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Kalchishkova, Nikolina: The role of the neck linker and neck in kinesin velocity regulation. 2009.

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