Kinesin 1 is a molecular motor protein that serves as a cellular “transportation system.” It is a member of the kinesin superfamily, which consists of 14 subfamilies. Also known as conventional kinesin, it moves various cellular components along specific tracks, playing a role in maintaining cell organization and function.
The Molecular Motor’s Design and Movement
Kinesin 1 is a heterotetramer, composed of two heavy chains (KHC) and two light chains (KLC). Heavy chains are responsible for motor activity, while light chains are involved in cargo binding and regulating the motor. Each heavy chain features a globular motor domain at its N-terminus, containing sites for ATP binding and microtubule attachment.
A long, central coiled-coil stalk connects the motor domain to the tail, facilitating heavy chain dimerization. A flexible neck linker of approximately 14 residues joins the motor domain to the stalk; conformational changes within this linker are central to the protein’s movement. The tail domain binds cellular “cargo,” often through interactions with the light chains.
Kinesin 1 “walks” along microtubules in a hand-over-hand manner, powered by the hydrolysis of adenosine triphosphate (ATP). As one motor head binds to a beta-tubulin subunit, it releases adenosine diphosphate (ADP), becoming the “leading head.”
ATP binding to the leading head induces a conformational change, causing the neck linker to swing forward and propel the trailing head. This head then binds the next beta-tubulin subunit, releases its ADP, and the cycle repeats. Each step moves kinesin 1 approximately 8 nanometers. This processive movement allows kinesin 1 to travel long distances unidirectionally towards the microtubule’s plus end, away from the cell’s center.
Essential Functions in Cell Transport
Kinesin 1 transports various cellular cargo as an anterograde motor. This includes organelles such as mitochondria, transported along microtubules to maintain their proper distribution and function. Kinesin 1 also transports lysosomes to the cell’s periphery for degradation and recycling, and is involved in shaping the endoplasmic reticulum network.
Vesicles carrying various substances, including neurotransmitters, hormones, and waste products, are moved by kinesin 1. The protein facilitates the transport of proteins and mRNA molecules, important for localized protein synthesis and cellular signaling. For example, kinesin 1 transports oskar mRNA to the posterior pole of the Drosophila oocyte, a process relying on specific cargo adaptors.
Kinesin 1 plays a role in axonal transport within neurons, moving materials from the cell body towards axon tips. This long-distance transport delivers newly synthesized proteins, lipids, and organelles to distant neuron parts, supporting nerve cell development, growth, and communication. Kinesin 1 also contributes to cell division, influencing mitotic spindle assembly and chromosome segregation, and can mediate microtubule-microtubule sliding to drive changes in cell shape.
Kinesin 1’s Role in Health and Disease
When kinesin 1 function is impaired, it can have consequences for cellular health, particularly in neurons. Defects in kinesin 1-mediated transport are associated with various neurodegenerative diseases. This is due to neurons’ reliance on efficient axonal transport to maintain their structure and function, given their elongated axons.
In Alzheimer’s disease (AD), impaired axonal transport and kinesin 1 dysfunction contribute to synaptic impairment and cognitive decline. Studies show reduced levels of kinesin light chain 1 (KLC1) in AD, affecting cellular component movement along axons. Abnormal accumulation of hyperphosphorylated tau protein, an AD hallmark, can also interfere with kinesin 1’s ability to bind to microtubules and transport cargo, exacerbating neuronal dysfunction.
Kinesin 1 dysfunction is also observed in Parkinson’s disease (PD) and Huntington’s disease (HD). In PD, early axonal dysfunction and motor protein loss are noted, with misfolded alpha-synuclein impacting axonal transport. In HD, mutant huntingtin protein disrupts axonal transport, contributing to neuronal degeneration and symptoms like abnormal movements and cognitive decline. These transport deficits can occur early in disease progression, underscoring kinesin 1’s role in neuronal health.