Molecular determinants of KA1 domain-mediated autoinhibition and phospholipid activation of MARK1 kinase

摘要: Protein kinases are frequently regulated by intramolecular autoinhibitory interactions between protein modules that reversed when these bind other ‘activating’ or membrane-bound targets. One group of kinases, the M AP/ m icrotubule a ffinity- r egulating k inases (MARKs) contain poorly understood regulatory module, KA1 ( inase ssociated-1) domain, at their C-terminus. domains from MARK1 and several related yeast to humans have been shown membranes containing anionic phospholipids, peptide ligands also reported. Deleting mutating C-terminal domain has reported activate kinase in which it is found — suggesting an role. Here, we show human interacts with, inhibits, domain. Using site-directed mutagenesis, identify residues required for this activity, find involved autoinhibition phospholipid binding same. We demonstrate ‘mini’ becomes activated upon association with vesicles but only if targeted second signal. These studies provide mechanistic basis understanding how its relatives may require more than one signal membrane surface control activation correct location time. MARK family implicated plethora disease states including Alzheimer9s, cancer, autism, so advancing our mechanisms ultimately therapeutic value.