ReMAPping the microtubule landscape: How phosphorylation dictates the activities of microtubule-associated proteins

Abstract

Classical microtubule-associated proteins (MAPs) were originally identified based on their co-purification with microtubules assembled from mammalian brain lysate. They have since been found to perform a range of functions involved in regulating the dynamics of the microtubule cytoskeleton. Most of these MAPs play integral roles in microtubule organization during neuronal development, microtubule remodeling during neuronal activity, and microtubule stabilization during neuronal maintenance. As a result, mutations in MAPs contribute to neurodevelopmental disorders, psychiatric conditions, and neurodegenerative diseases. MAPs are post-translationally regulated by phosphorylation depending on developmental time point and cellular context. Phosphorylation can affect the microtubule affinity, cellular localization, or overall function of a particular MAP and can thus have profound implications for neuronal health. Here we review MAP1, MAP2, MAP4, MAP6, MAP7, MAP9, tau, and DCX, and how each is regulated by phosphorylation in neuronal physiology and disease. Developmental Dynamics 247:138-155, 2018. © 2017 Wiley Periodicals, Inc.

Keywords: MAPs; cytoskeleton; kinases; microtubules; neurodegeneration; neuronal development.

Figure 1. Domain organization of microtubule-associated proteins (MAPs)

The microtubule-binding domains (yellow), actin-binding domains (blue), kinase domains (green), and phosphorylation sites (blue stars) are illustrated for each MAP. Note that the phosphorylation sites of DCLK1 are proposed autophosphorylation sites. The following accession numbers for the protein sequences were used for this schematic: NP_002364.5 for MAP1A, NP_005900.2 for MAP1B, NP_060644.4 for MAP1S, NP_002365.3 for MAP2A/B, NP_114033.2 for MAP2C, NP_001127836.1 for MAP4, NP_149052.1 for MAP6, NP_001185537.1 for MAP7, NP_001034669.1 for MAP9, NP_005901.2 for tau, NP_001317001.1 for DCLK, and NP_835365.1 for DCX.

Figure 2. Model for the effect of phosphorylation on each MAP

Based on the literature reviewed here, there are different classes of phosphorylation effects on MAP activity. Phosphorylation of MAP1B and MAP7 do not seem to affect their ability to bind the microtubule, while phosphorylation of DCX, MAP4, Tau, MAP2, and MAP6 all release from the microtubule upon phosphorylation. MAP2 and MAP6 re-localize to actin-rich regions with the cell, but how these MAPs bind actin is unknown.

Figure 3. Phosphorylated residues in tubulin using the PDB structure, 1TUB

(A) The structure of the tubulin heterodimer highlighting the two residues that, upon phosphorylation, inhibit microtubule polymerization. S172 (in pink) is located near the GTP binding pocket of beta-tubulin (in gray). T349 (in red) is located within alpha-tubulin at the binding interface. The sequence that precedes the C-terminal tails (CTTs) is colored in cyan. (B) The structure of the tubulin heterodimer highlighting one potential tyrosine residue that is exposed on alpha-tubulin that could be a target of phosphorylation.