Evolution of Kinesin and Myosin Motors, and the Roles They Play In Degenerative Diseases - PowerPoint PPT Presentation

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Evolution of Kinesin and Myosin Motors, and the Roles They Play In Degenerative Diseases
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Evolution of Kinesin and Myosin Motors, and the Roles They Play In Degenerative Diseases

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  1. Evolution of Kinesin and Myosin Motors, and the Roles They Play In Degenerative Diseases • By: Lauren Kaiser

  2. Objectives • Evolution of myosin • Evolution of kinesin • Divergence of kinesin and myosin motors • Degenerative diseases

  3. Myosin Review • Motor proteins • Function on actin filaments • Plus end directed • Muscle contraction • Vision • Hearing • Responsible for overall cell motility http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/images/myosinVstr.gif

  4. How myosin generate movement • ADP+Pi bound state • creating a weak affinity for actin • Head domain docks on actin • Pi is released • creating tight affinity for actin • generating the power stroke • ADP dissociates • ATP binds at empty nucleotide binding site • Causing head to release • ATP is hydrolyzed • re-cocking motor to pre-stroke state

  5. Evolution of myosin • Developed in eukaryotic organisms • Based on need for cell motility, vision, hearing • Well conserved head domains • 18 different classes • gene duplication lead the divergence of these classes • Classes I and II are the most diverse • Carry out more generalized functions • Later diverging classes have more specific functions and are restricted to specific organisms • Common origin between classes II and XVIII as well as XII and XV

  6. https://intramural.nhlbi.nih.gov/labs/LMP/Picture%20Library/2010-%20myosin%20tree%202009.JPGhttps://intramural.nhlbi.nih.gov/labs/LMP/Picture%20Library/2010-%20myosin%20tree%202009.JPG

  7. Kinesin Review • Motor Protein • Function on microtubules • Plus end directed • movement from center out • Cell division • Cargo transport • Axonal transport • Cell motility

  8. How kinesin generate movement • Tightly bound ADP • ADP is released once bound to microtubule • ATP rapidly binds at nucleotide binding site • Triggers neck linker to zipper onto catalytic core • Second head thrown forward • Trailing head hydrolyzes ATP • Pi is released and first head is thrown forward

  9. Evolution of kinesin • 11 Classes that make up this superfamily • 1624 domains have been identified • Highly preserved motor domains • Each has there own specific function • Divergence supports phenomena

  10. http://www.proweb.org/kinesin/Images/kinesintree.jpg

  11. Structural similarities of myosin and kinesin • Similar molecular motors • Coiled coil • Globular head domains http://www.grin.com/object/external_document.250976/22dae50eab455a433773904e4a8b1853_LARGE.png

  12. Structural similarities of myosin and kinesin • Structural overlap • 6 alpha helices • 8:6 beta sheet http://valelab.ucsf.edu/images/res-kinesin/fig05.jpg

  13. Structural similarities of myosin and kinesin • Location of catalytic binding site http://valelab.ucsf.edu/images/res-kinesin/fig34.jpg

  14. Functional similarities of myosin and kinesin • Plus end directed motors • ATPase • Movement generation (power stroke) • Kinesin has tight affinity for its track in ATP bound state • Myosin has tight affinity for track in ADP bound state • Cargo transporters

  15. What does this all mean? • EVOLUTION! • Divergence • Widely accepted • Structural and functional similarities http://stuff.mit.edu/afs/athena/course/other/beh.410/OldFiles/www/Handouts/vale.pdf

  16. Amyotrophic Lateral Sclerosis (ALS) • Lou Gehrig’s Disease • Neuromuscular disease • Fatal and rapid progression • 2-5 years • 2 types of ALS • Sporadic: 90-95% of cases • Familial: 5-10% of cases http://charlespaolino.files.wordpress.com/2011/02/gehrig-lou-1.jpg

  17. Symptoms • Late onset • 40-60 years of age • Muscle weakness • Muscle spasms or twitching • Loss of function in arms and legs • Difficulty speaking, chewing, swallowing and breathing • Respiratory failure

  18. ALS and kinesin • Familial ALS • Slowing of axonal transport • Studied in cultured cells and affected tissues in mice • SOD1 mutation • Interacting and interferes with kinesin • Hindering axonal transport of cargo • Ultimately the cause behind motor neuron death in Familial ALS

  19. Why is this important? • Still don’t know how exactly SOD1 directly affects axonal motor protein • Just beginning to understand the roles of motor protein in disease • potential secondary affects on myosin motors • Preventative measure • Genetic testing • Linked to more and more diseases

  20. Other diseases linked to motor proteins • Kinesin related diseases • Alzheimer’s • Parkinson's • Myosin related diseases • Muscular dystrophy • Degeneration of optic nerves • Hearing loss