Kinase Associated-1 Domains Drive MARK/PAR1 Kinases to Membrane Targets by Binding Acidic Phospholipids

Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA.
Cell (Impact Factor: 32.24). 12/2010; 143(6):966-77. DOI: 10.1016/j.cell.2010.11.028
Source: PubMed


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.

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    • "Our studies on human cultured cells showed that a part of the MELK kinase regulatory domain, (the C-terminal domain, which includes the KA1 domain, Kinase Associated domain 1), is involved in MELK localization at the cell cortex during mitosis (Chartrain et al., 2006). In agreement with our finding, it has been recently shown that in various kinases, including MELK, the KA1 domain is responsible for their association with cellular membranes (Moravcevic et al., 2010). However, the higher concentration of iMELK at the cell–cell contacts in epithelial cells led us to hypothesize that iMELK may interact with a putative partner present in this particular subcellular location. "
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