Evolution of Kinesin and Myosin

Motors, and the Roles They Play In

Degenerative Diseases

By: Lauren Kaiser

Objectives

•Evolution of myosin

•Evolution of kinesin

•Divergence of kinesin and myosin motors

•Degenerative diseases

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

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

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

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

Kinesin Review•Motor Protein

•Function on microtubules

•Plus end directed

• movement from center out

•Cell division

•Cargo transport

•Axonal transport

•Cell motility

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

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

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

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

Structural similarities of

myosin and kinesin•Structural

overlap

•6 alpha helices

•8:6 beta sheet

http://valelab.ucsf.edu/images/res-kinesin/fig05.jpg

Structural similarities of

myosin and kinesin

•Location of catalytic binding site

http://valelab.ucsf.edu/images/res-kinesin/fig34.jpg

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

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

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

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

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

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

Other diseases linked to motor

proteins•Kinesin related diseases

•Alzheimer’s

•Parkinson's

•Myosin related diseases

•Muscular dystrophy

•Degeneration of optic nerves

•Hearing loss