Microtubule and molecular motors Flashcards
Why is the delivery process for proteins in neurons more complex?
Distance
Constant requirement for new protein components and organelles
synaptic signals and old components need to be returned to cell body for degradation
What do cytoskeletal structures form?
Tracks that components are trafficked along
What do molecular motors do?
Trafficking
What 3 fibrillar elements make up the cytoskeleton?
Microtubules
Neurofilaments
Microfilaments
What makes up microtubule walls?
13 protofilaments formed by linear arrangement of heterodimers of alpha and beta tubulin molecules
What end of microtubules is GTP-bound tubulin added to?
Plus ends
How are MTs formed in dendrites and axons?
Nucleation at MT organising centre
Then release to migrate into axons or dendrites
Where are MTs less regularly aligned?
Dendrites
What is MT treadmilling?
Dynamic behavior which tubulin molecules bound to GDP are continually lost from - end and replaced on + end
What weakens the binding of tubulin for adjacent molecules and causes dynamic instability?
GTP hydrolysis
What is dynamic instability?
Individual microtubules alternate between cycles of growth and shrinkage
What determines dynamic instability?
Rate of tubulin addition relative to rate of GTP hydrolysis
What post-translational modifications do some MT regions undergo?
acetylation of alpha tubulin
Phosphorylation of beta tubulin
What do microtubule-associates proteins do?
Bind to MT surfaces and alter their assembly and stability
What do high molecular weight MAPs have?
Distinct localizations
What do tau proteins do?
Line MT and form links with adjacent MTs - facilitates MT stabilization within cells
What happens in Alzheimer’s disease with tau proteins?
Tau is hyperphosphorylated and sequestered into neurofibrillary tangles - less tau to bind MT
MT instability and reduced axonal transport
What are neurofilaments (NF) main function?
Provide structural support for the axon and regulate axon diameter
How are NFs formed?
Fibers twist around eachother - form monomers
Monomoers form coiled-coil heterodimers
Dimers form tetrameric complex - forms protofilament
2 protofilaments -> protofibril -> 3 protofibrils -> neurofilament
What causes NFs to be disrupted in Alzheimers?
Lesion called neurofibrillary tangle
How are microfilaments formed?
2 strands of polymerised actin monomers and are polar
How are microfilaments dynamics regulated?
Treadmilling
Where are microfilaments most abundant in neurons?
Presynaptic terminals, dendritic spines and growth cones
are present in cytoplasm
What 4 proteins are associated with microfilaments?
Myosin/tropomyosin
Capping proteins - anchor
Microfilament severing proteins - reorganise actin cytoskeleton
Cross-linking proteins - bundle microfilaments
What 3 families of proteins are molecular motors derived from?
Kinesin
Dynein
Myosin
What are the 3 differences of molecular motors?
Can work as single molecules or large assemblies
Undergo linear motion or rotate around axis
Drive subcellular transport from a few micrometers up to a metre
What are 3 common features of molecular motors?
Undergo energy-dependent conformational changes
Unidirectional movement
All consist of a dimer of 2 heavy chains with catalytic motor domains and a stalk region
What does Kinesins’ heavy chain consist of?
ATP and MT binding domains
What do kinesins move towards?
Plus end of MTs
What is the most common kinesin expressed in the brain?
Kinesin-1
What causes Kinesin movement?
ATP hydrolysis
What do mutations in KIF1B cause?
Hereditary neuropathy Charcot-Marie-Tooth
What 2 dyneins make up the dynein superfamily?
Cytoplasmic and cilary dyneins
What two binding domains are present in dynein’s heavy chains?
ATP and MT
What is dynein’s function?
Mediate cellular transport by ATP hydrolysis
In what direction do dyneins move?
Minus end of MT
What important associated protein complex does cytoplasmic dynein have?
Dynactin
What does Dynactin do?
Regulates dynein activity and cargo binding capacity
What does loss of cytoplasmic dynein cause?
Disrupts neuronal trafficking and degeneration of motor neurons
What is myosin’s function?
Roles in neuronal growth and development and specialised cells (sensory hair cells of cochlea)
What do myosin’s heavy chain consist of?
ATP binding site
What regulates motor function in myosin?
Divergent light chains
What do myosins use to move components along actin?
Energy from ATP hydolysis
What is axonal transport processes crucial for?
Neuronal development, plasticity and degeneration
What transport is slow transport?
Anterograde transport
What transport is fast transport?
Anterograde and retrograde transport
What does slow component a move?
Cytoskeletal elements as polymers
What type of movement does slow component a exhibit?
Discontinuous movement
What does slow component b move?
soluble enzymes and cytoskeletal proteins
What is slow component b a rate limiting component of?
Nerve growth or regeneration
What is fast anterograde transport?
Movement of membrane bound organelles (MBOs) along MTs away from cell body
What does fast anterograde transport provide?
Newly synthesized components to synapses
What needs the material transported by fast anterograde transport?
Supply and turnover of intracellular membrane compartments
Secretory products
Proteins needed for axonal metabolism
What does fast retrograde transport move?
larger and more heterogeneous MBOs
Where is fast retrograde transport thought to transport material to?
Material to be delivered to lysosomes eg. Growth factors
How does size affect rate of transport?
Larger the size the more drag due to interactions with cytoplasmic structures
How is coordination of opposing motors regulated?
Phosphorylation of motor proteins or their cargoes
How is targeting of certain proteins to discrete regions of the neuron regulated?
Local changes in balance between kinase and phosphatase activity in subdomains act on motor proteins
