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KIF1A Motor Domain

Introduction

The KIF1A motor domain is a segment of the Kinesin-like protein KIF1A which is a motor protein. Kinesin is a microtubule motor that transports "cargo" by "walking" along a microtubule track. In KIF1A's case, it is a motor for anterograde axonal transport of synaptic vesicle precursors. The motor domain is what gives kinesin it's mobility. It does this by hydrolyzing ATP which changes kinesin's structure and, in turn, generates movement down the track. For the majority, it is found in adult brain tissue (the cerebellum and cerebrum) within one specific type of neuronal cell. The KIF1A motor domain serves the same function wherever KIF1A is found, this includes humans and mice. Motor proteins(including their motor domains) are also utilized by types of fungi, plants, mammals, and insects. Defects with the KIF1A protein can result in spastic paraplegia, sensory neuropathy, and mental retardation.

Structure

The KIF1A motor domain is a subunit of the KIF1A transport protein. The domain's secondary structures consist of a and eight . The motor domain uses as a ligand and energy source. The motor domain gets energy from the breaking of the phosphorous-phosphorous bond in the ATP. Located in between amino acids 323-332 is the neck linker. The KIF1A motor domain is mapped using a combination of x-ray crystallography and cryo-electron microscopy which analyzes force-generating conformation changes at atomic resolution.

Mechanism of Action

Molecular motors connect the change of breaking ATP phosphate-phosphate bonds into structural change of the motor itself. When the, now, ADP is cleaved and the phosphate group dissociates, the ATP binding site changes. This change pushes on the relay helix which causes the motor to change conformation. As it changes, and the "power stroke" occurs and a pocket forms. This pocket allows the neck linker to "zip" into the protein of the track, pulling it along with it's attached cargo. Kinesin has two motor domains side by side, which is why the term "walking" is used to describe kinesin's movement down the track.

Medical Implications or Possible Application

Defects in the KIF1A protein include: spastic paraplegia autosomal recessive type 30 (SPG30), hereditary sensory neuropathy type 2C (HSN2C), and mental retardation autosomal dominant type 9 (MRD9).

Spastic paraplegia autosomal recessive type 30, or SPG30, is a type of spastic paraplegia. Spastic paraplegia is a neurodegenerative disorder that is characterized by gradual weakness and lower back spasms. The severity of the symptoms and the rate of progression range from case to case. At first, balancing becomes difficult and stiffness and weakness occurs in the legs. This also leads to muscle spasms and dragging of the toes. The SPG30 spreads through the body, loss of bladder function and stiffness of other body parts can occur.

Hereditary Sensory Neuropathy Type 2C, or HSN2C, is a neurodegenerative disorder that is characterized after a decade of progressive sensory loss in outer body parts, such as the fingers and toes. This sensory loss can lead to ulceration and amputation of these body parts. Also, muscle weakness in the legs and feet is common.

Mental Retardation Autosomal Dominant Type 9, or MRD9, is characterized by below average intellectual function along with a lack of adaptive behavior.

References

http://www.rcsb.org/pdb/results/results.do?qrid=F4B2AD40&tabtoshow=Current http://www.uniprot.org/uniprot/Q12756 https://valelab.ucsf.edu/publications/2000casecurrbiol.pdf http://www.rcsb.org/pdb/explore.do?structureId=1I5S www.uniprot.org/uniprot/F5H045 http://www.rcsb.org/pdb/explore.do?structureId=1I5S