Kinases of the MARK/Par-1 family of S/T protein kinases are regulators of diverse cellular processes in Caenorhabditis elegans, Drosophila, yeast, and mammalian cells. They are involved in nematode embryogenesis, epithelial cell polarization, cell signaling, and neuronal differentiation. MARK phosphorylates microtubule-associated proteins such as tau and is a key regulator of microtubule-based intracellular transport. Hyperphosphorylation of tau causes defects in neuronal transport and may induce abnormal aggregation of tau in Alzheimer disease and other tauopathies. Recent high-resolution structure analysis of MARK fragments covering the kinase domain and accessory regulatory domains has revealed important details regarding the autoregulation of MARK, but their interpretation has remained controversial. Here we focus on the structural aspects of MARK activity and autoregulation. Comparison of the available MARK structures with related kinases of the AMPK family and with new structures of MARK isoforms (MARK2 and 3) reveals unexpected structural similarities between these kinases that may help to resolve the existing controversies.

Here we report the crystal structure of the catalytic and UBA domain of another isoform, MARK1. Although the crystal packing of the two isoforms are unrelated, the overall conformations of the molecules are similar. Notably, the UBA domain has the same unusual conformation as in MARK2, and it binds at the same site. Remarkable differences occur in the catalytic domain at helix C, the catalytic loop, and the activation segment.The Ser/Thr kinase MARK 2 has been identified by the ability to phosphorylate tau at certain serine residues in the microtubule binding repeats (1). Phosphorylation of tau and other microtubule-associated proteins (MAP2, MAP4) at the KXGS motifs by MARK reduces the affinity to microtubules and leads to microtubule disassembly. Hyperphosphorylation of tau followed by aggregation to paired helical filaments is one of the hallmarks of Alzheimer disease. MARK orthologues KIN1 in fission yeast and Par-1 in Drosophila and Caenorhabditis elegans are involved in the development of cell polarity (2, 3). In neurons, MARK is required for neurite outgrowth and differentiation (4).There are four isoforms of MARK in the human kinome that form a subfamily of the Snf1/AMP-activated protein kinase family of kinases within the calcium/calmodulin-dependent protein kinase group (5). MARK kinases are relatively large; the longest isoform, MARK1, comprises 795 amino acids (Fig. 1). The catalytic domain is flanked by an N-terminal header of about 60 amino acids and a linker of about 20 amino acids that includes a four-residue motif (adjacent to the catalytic domain) that may serve as a common docking site (CD domain) for regulatory binding partners in analogy to MAP kinases (6). The linker connects the catalytic domain to a bona fide UBA (ubiquitin-Associated) domain, a globular domain of 40 amino acids consisting of three ␣-helices. The UBA domain is followed by a long spacer and a globular tail (NMR structure, see Protein Data Bank code 1UL7) that comprises the KA1 domain (kinasesassociated domain 1) with the characteristic ELKL motif at the C terminus. The functions of the putative UBA and KA1 domains are not well understood. The fact that most of the AMP-activated protein kinase-related kinases, including the yeast homologue Snf1, possess a UBA or UBA-like domain (7, 8) suggests a conserved function in structural stabilization or regulation of kinase activity.Like many other kinases, MARK is regulated by phosphorylation of the activation loop (T-loop). MARKK/TAO-1 (9) and the tumor suppressor kinase LKB1/Par-4 (10, 11) activate MARK by phosphorylation of the T-loop. A fraction of MARK isolated from brain tissue is doubly phosphorylated at Thr-208 and Ser-212 (MARK2 numbering used throughout); phosphorylation of the second site, however, is inhibitory (9). There are a number of other mechanisms that seem to be able to regulate MARK, including phosphorylation of the spacer by atypical * The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be ...

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