TY - JOUR
T1 - Kinase associated-1 domains drive MARK/PAR1 kinases to membrane targets by binding acidic phospholipids
AU - Moravcevic, Katarina
AU - Mendrola, Jeannine M.
AU - Schmitz, Karl R.
AU - Wang, Yu Hsiu
AU - Slochower, David
AU - Janmey, Paul A.
AU - Lemmon, Mark A.
N1 - Funding Information:
We thank members of the Lemmon, Ferguson, and Bi laboratories and Ben Black, Jim Shorter, and Greg Van Duyne for constructive comments. Erfei Bi, Scott Emr, and Daryll DeWald provided yeast strains used in this study. Crystallographic data were collected in part at the GM/CA Collaborative Access Team at the Advanced Photon Source (APS), funded by NCI (Y1-CO-1020) and NIGMS (Y1-GM-1104). Use of APS was supported by the U.S. Department of Energy, under contract No. DE-AC02-06CH11357. Additional crystallographic data were collected at beamline F2 at the Cornell High Energy Synchrotron Source (CHESS), supported by NIGMS and the NSF (under award DMR-0936384), using the Macromolecular Diffraction at CHESS (MacCHESS) facility, supported by the NIH (award RR-01646). This work was funded in part by NIH grant R01-GM056846 (to M.A.L.) and a predoctoral fellowship from the American Heart Association Great Rivers Affiliate (K.M.).
PY - 2010/12/10
Y1 - 2010/12/10
N2 - 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. PaperClip:
AB - 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. PaperClip:
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U2 - 10.1016/j.cell.2010.11.028
DO - 10.1016/j.cell.2010.11.028
M3 - Article
C2 - 21145462
AN - SCOPUS:78649915767
SN - 0092-8674
VL - 143
SP - 966
EP - 977
JO - Cell
JF - Cell
IS - 6
ER -