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#microtubule stability

2 public questions tagged with this topic.

Cytoskeleton

Which microtubule-binding protein suppresses catastrophe and promotes stability?

Stable microtubule subsets resist cold and nocodazole depolymerization due to decoration by classical structural MAPs reducing dynamics. Members include MAP2 and tau families as well as MAP1B and CLASP. MAP2 specifically expressed in neurons predominantly dendritic compartment forms projection domain protruding from filament serving as spacing crosslinker and microtubule binding repeats with positive charge neutralizing acidic tubulin C terminal tails bridging adjacent protofilaments reinforcing lateral contacts mechanically stiffening filament suppressing catastrophe by maintaining straight lattice conformation resisting GDP induced curling. Activity promotes rescue and long lived polymer essential for dendrite morphogenesis. Modulated by phosphorylation through MARK CDK5 reducing affinity to allow remodeling during branching and synaptic plasticity. CLASP also suppresses catastrophe at plus ends but MAP2 binds along lattice providing continuous stability. Katanin severs rather than stabilizes tau similar to MAP2 in axons. Therefore MAP2 exemplifies microtubule binding protein that suppresses catastrophe promotes stability crucial for dendrite outgrowth and plasticity maintenance and transport fidelity.

Ref: Dehmelt & Halpain, Genome Biology 2005 – MAP2 suppresses catastrophe promoting stability via lattice binding.

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Cytoskeleton

What happens when Tau proteins are hyperphosphorylated?

Tau is neuronal MAP enriched in axons that normally binds acidic C terminal tails of tubulin along microtubule outer ridges spacing and stabilizing bundles required for efficient axonal transport of vesicles and mitochondria. Repeat domains R1 to R4 plus flanking proline rich regions interact with lattice through electrostatic plus hydrophobic contacts promoting assembly reducing catastrophe. Phosphorylation introduces negative charge repulsing interaction and altering conformation. In normal physiology limited phosphorylation dynamically modulates affinity allowing plasticity. Hyperphosphorylation by proline directed kinases GSK3 beta CDK5 MARK on multiple serine threonine residues within repeat and flanking regions dramatically reduces microtubule binding affinity by 10 fold causing tau to detach extensively. Detached phospho tau prone to misfold into beta sheet rich paired helical filaments composing neurofibrillary tangles characteristic of Alzheimer pathology. Consequently microtubules lose stability undergo increased catastrophe and disassembly impairing kinesin dynein trafficking synaptic maintenance leading to neurodegeneration and cognitive decline emphasizing stability role of tau.

Ref: Mandelkow & Mandelkow, Trends Cell Biol 2012 – Hyperphosphorylated tau detaches leads to microtubule disassembly.

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