The MAP2/Tau family of microtubule-associated proteins

Abstract

Microtubule-associated proteins (MAPs) of the MAP2/Tau family include the vertebrate proteins MAP2, MAP4, and Tau and homologs in other animals. All three vertebrate members of the family have alternative splice forms; all isoforms share a conserved carboxy-terminal domain containing microtubule-binding repeats, and an amino-terminal projection domain of varying size. MAP2 and Tau are found in neurons, whereas MAP4 is present in many other tissues but is generally absent from neurons. Members of the family are best known for their microtubule-stabilizing activity and for proposed roles regulating microtubule networks in the axons and dendrites of neurons. Contrary to this simple, traditional view, accumulating evidence suggests a much broader range of functions, such as binding to filamentous (F) actin, recruitment of signaling proteins, and regulation of microtubule-mediated transport. Tau is also implicated in Alzheimer's disease and other dementias. The ability of MAP2 to interact with both microtubules and F-actin might be critical for neuromorphogenic processes, such as neurite initiation, during which networks of microtubules and F-actin are reorganized in a coordinated manner. Various upstream kinases and interacting proteins have been identified that regulate the microtubule-stabilizing activity of MAP2/Tau family proteins.

Figure 1

Phylogenetic analysis of MAP2/Tau family proteins. Homologous protein sequences of the microtubule-binding repeats of MAP2 (using splice forms (with three microtubule-binding repeats), Tau (four-repeat isoforms), MAP4 (five-repeat isoforms) and the invertebrate MAPs CG31057 and PTL-1A (five-repeat isoforms) were analyzed using the program Phylip 76; gaps were ignored. The available Tetraodon sequences are incomplete and were therefore not included in the analysis.

Figure 2

The domain organization of MAP2/Tau family proteins. Selected isoforms of the human members of the family are shown, as well as the nematode homolog PTL-1. All family members have alternative splice forms with varying numbers of carboxy-terminal microtubule-binding repeats and amino-terminal projection domains of varying lengths. PKA (RII) indicates a domain interacting with the RII subunit of protein kinase A. Repeats that are not present in all major isoforms are shown lighter.

Figure 3

A neuron from a culture of rat brain hippocampus, showing the distinct subdomains of MAP2 and Tau enrichment in mature neurons. MAP2 is found specifically in dendrites (arrow), whereas Tau is mainly axonal (arrowhead). Note the fine meshwork of axons from neighboring cells outside the field of view that make numerous synaptic connections among the neurons in the culture.