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The kinesin dimer attaches to, and moves along, microtubules.
Diagram illustrating motility of kinesin.

Kinesins are a class of motor proteins found in eukaryotic cells. Kinesins move along microtubule cables powered by the dephosphorylation of ATP (thus kinesins are ATPases). The active movement of kinesins supports several cellular functions including mitosis, meiosis and transport of cargo such as axonal transport.

Contents

Structure

Kinesins (the one shown is from PDB 3kin) and dyneins walk along microtubules dragging their cargo along with them (red: ATP) (bottom: domain that links to the cargos) (more details...)
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Overall structure

Members of the kinesin family vary in shape but the typical kinesin is a protein dimer (molecule pair) consisting of two heavy chains and two light chains. The heavy chain comprises a globular head (the motor domain) connected via a short, flexible neck linker to the stalk - a long, central coiled-coil stalk - that ends in a tail region formed with a light-chain. The stalks intertwine to form the kinesin dimer. Cargo binds to the tail region.

Kinesin motor domain

Kinesin motor domain
Kinesin motor domain 1BG2.png
Crystallographic structure of the human kinesin motor domain depicted as a rainbow colored cartoon (N-terminus = blue, C-terminus = red) complexed with ADP (stick diagram, carbon = white, oxygen = red, nitrogen = blue, phosphorous = orange) and a magnesium ion (grey sphere).[1]
Identifiers
Symbol Kinesin motor domain
Pfam PF00225
InterPro IPR001752
SMART SM00129
PROSITE PS50067
SCOP 1bg2

The head is the signature of kinesin and its amino acid sequence is well conserved among various kinesins. Each head has two separate binding sites: one for the microtubule and the other for ATP. ATP binding and hydrolysis as well as ADP release change the conformation of the microtubule-binding domains and the orientation of the neck linker with respect to the head; this results in the motion of the kinesin. Several structural elements in the head, including a central beta-sheet domain and the Switch I and II domains, have been implicated as mediating the interactions between the two binding sites and the neck domain. Kinesins are related structurally to G proteins, which hydrolyze GTP instead of ATP. Several structural elements are shared between the two families, notably the Switch I and Switch II domains.

Cargo transport

In the cell, small molecules such as gases and glucose diffuse to where they are needed. Large molecules synthesised in the cell body, intracellular components such as vesicles, and organelles such as mitochondria are too large (and the cytosol too crowded) to diffuse to their destinations. Motor proteins fulfill the role of transporting large cargo about the cell to their required destinations. Kinesins are motor proteins that transport such cargo by walking unidirectionally along microtubule tracks hydrolysing one molecule of adenosine triphosphate (ATP) at each step.[2] It was thought that ATP hydrolysis powered each step, the energy released propelling the head forwards to the next binding site.[3] However, it has been proposed that the head diffuses forward and the force of binding to the microtubule is what pulls the cargo along.[4]

There is significant evidence that cargoes in-vivo are transported by multiple motor.[5][6][7][8]

Direction of motion

Motor proteins travel in a specific direction along a microtubule. This is because the microtubule is polar and the heads only bind to the microtubule in one orientation, while ATP binding gives each step its direction through a process known as neck linker zippering.[9]

Most kinesins walk towards the plus end of a microtubule which, in most cells, entails transporting cargo from the centre of the cell towards the periphery. This form of transport is known as anterograde transport. Kinesin-14 family proteins, such as Drosophila NCD, budding yeast KAR3, and Arabidopsis ATK5, walk in the opposite direction, toward microtuble minus ends[10].


A different type of motor protein known as dyneins, move towards the minus end of the microtubule. Thus they transport cargo from the periphery (terminal buttons) of the cell towards the centre (soma). This is known as retrograde transport.

Proposed mechanisms of movement

Kinesin accomplishes transport by "walking" along a microtubule. Two mechanisms have been proposed to account for this movement.

  • In the "hand-over-hand" mechanism, the kinesin heads step past one another, alternating the lead position.
  • In the "inchworm" mechanism, one kinesin head always leads, moving forward a step before the trailing head catches up.

Despite some remaining controversy, mounting experimental evidence points towards the hand-over-hand mechanism as being more likely.[11][12]

Kinesin and mitosis

In recent years, it has been found that microtubule-based molecular motors (including a number of kinesins) have a role in mitosis (cell division). The mechanism by which the cytoskeleton of the daughter cell separates from that of the mother cell was unclear. It seems that motors organize the two separate microtubule asters into a metastable structure independent of any external positional cues. This self-organization is in turn dependent on the directionality of the motors as well as their processivity (ability to walk). Thus motors are necessary for the formation of the mitotic spindle assemblies that perform chromosome separation. Specifically, proteins from the Kinesin 13 family act as regulators of microtubule dynamics. The prototypical member of this family is MCAK (formerly Kif2C, XKCM1, Gene KIF2C) which acts at the ends of microtubule polymers to depolymerize them. The function of MCAK in cells and its mechanism in vitro is currently being investigated by numerous labs.

Family members

Human kinesin family members include:

light chains:

See also

References

  1. ^ PDB 1BG2; Kull FJ, Sablin EP, Lau R, Fletterick RJ, Vale RD (April 1996). "Crystal structure of the kinesin motor domain reveals a structural similarity to myosin". Nature 380 (6574): 550–5. doi:10.1038/380550a0. PMID 8606779.  
  2. ^ Schnitzer MJ, Block SM (1997). "Kinesin hydrolyses one ATP per 8-nm step". Nature 388: 386–390. doi:10.1038/41111. PMID 9237757.  
  3. ^ Vale RD, Milligan RA (April 2000). "The way things move: looking under the hood of molecular motor proteins". Science (journal) 288 (5463): 88–95. doi:10.1126/science.288.5463.88. PMID 10753125.  
  4. ^ Mather WH, Fox RF (2006). "Kinesin's Biased Stepping Mechanism: Amplification of Neck Linker Zippering". Biophysical Journal 91: 2416–2426. doi:10.1529/biophysj.106.087049. PMID 16844749.  
  5. ^ Gross SP, Vershinin M, Shubeita GT (June 2007). "Cargo transport: two motors are sometimes better than one". Current Biology : CB 17 (12): R478–86. doi:10.1016/j.cub.2007.04.025. PMID 17580082.  
  6. ^ Hancock WO (August 2008). "Intracellular transport: kinesins working together". Current Biology : CB 18 (16): R715–7. doi:10.1016/j.cub.2008.07.068. PMID 18727910.  
  7. ^ Kunwar A, Vershinin M, Xu J, Gross SP (August 2008). "Stepping, strain gating, and an unexpected force-velocity curve for multiple-motor-based transport". Current Biology : CB 18 (16): 1173–83. doi:10.1016/j.cub.2008.07.027. PMID 18701289.  
  8. ^ Klumpp S, Lipowsky R (November 2005). "Cooperative cargo transport by several molecular motors". Proceedings of the National Academy of Sciences of the United States of America 102 (48): 17284–9. doi:10.1073/pnas.0507363102. PMID 16287974.  
  9. ^ Rice S, Lin AW, Safer D, Hart CL, Naber N, Carragher BO, Cain SM, Pechatnikova E, Wilson-Kubalek EM, Whittaker M, Pate E, Cooke R, Taylor EW, Milligan RA, Vale RD (December 1999). "A structural change in the kinesin motor protein that drives motility". Nature 402 (6763): 778–84. doi:10.1038/45483. PMID 10617199.  
  10. ^ Ambrose JC,Li W, Marcus A, Ma H, Cyr R (2005). "A minus-end-directed kinesin with plus-end tracking protein activity is involved in spindle morphogenesis.". Molecular Biology of the Cell 16: 1584–1592. PMID 15659646.  
  11. ^ Yildiz A, Tomishige M, Vale RD, Selvin PR (2004). "Kinesin Walks Hand-Over-Hand". Science 303: 676–8. doi:10.1126/science.1093753. PMID 14684828.  
  12. ^ Asbury CL (2005). "Kinesin: world’s tiniest biped". Current Opinion in Cell Biology 17: 89–97. doi:10.1016/j.ceb.2004.12.002. PMID 15661524.  

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