title: Kinase associated-1 domains drive MARK/PAR1 kinases to membrane targets by binding acidic phospholipids.
abstract: Phospholipid-binding modules such as PH, C1, and C2 domains play crucial roles in location-dependent regulation of many protein kinases. Here, we identify the KA1 domain (kinase associated-1 domain), found at the C terminus of yeast septin-associated kinases (Kcc4p, Gin4p, and Hsl1p) and human MARK/PAR1 kinases, as a membrane association domain that binds acidic phospholipids. Membrane localization of isolated KA1 domains depends on phosphatidylserine. Using X-ray crystallography, we identified a structurally conserved binding site for anionic phospholipids in KA1 domains from Kcc4p and MARK1. Mutating this site impairs membrane association of both KA1 domains and intact proteins and reveals the importance of phosphatidylserine for bud neck localization of yeast Kcc4p. Our data suggest that KA1 domains contribute to "coincidence detection," allowing kinases to bind other regulators (such as septins) only at the membrane surface. These findings have important implications for understanding MARK/PAR1 kinases, which are implicated in Alzheimer's disease, cancer, and autism.
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA.
authors.forename: Katarina
authors.initials: K
authors.lastname: Moravcevic
authors.forename: Jeannine M
authors.initials: JM
authors.lastname: Mendrola
authors.forename: Karl R
authors.initials: KR
authors.lastname: Schmitz
authors.forename: Yu-Hsiu
authors.initials: YH
authors.lastname: Wang
authors.forename: David
authors.initials: D
authors.lastname: Slochower
authors.forename: Paul A
authors.initials: PA
authors.lastname: Janmey
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lemmon
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010743:Phospholipids / Q000378:metabolism*; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D010743:Phospholipids; D029701:Saccharomyces cerevisiae Proteins; D011494:Protein Kinases; C107283:GIN4 protein, S cerevisiae; C106494:HSL1 protein, S cerevisiae; C117190:KCC4 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases