Kinase associated-1 domains drive MARK/PAR1 kinases to membrane targets by binding acidic phospholipids.

Article Details

Citation

Moravcevic K, Mendrola JM, Schmitz KR, Wang YH, Slochower D, Janmey PA, Lemmon MA

Kinase associated-1 domains drive MARK/PAR1 kinases to membrane targets by binding acidic phospholipids.

Cell. 2010 Dec 10;143(6):966-77. doi: 10.1016/j.cell.2010.11.028.

PubMed ID
21145462 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Serine/threonine-protein kinase MARK1Q9P0L2Details
MAP/microtubule affinity-regulating kinase 3P27448Details
Maternal embryonic leucine zipper kinaseQ14680Details