GTPase function of Leucine rich repeat kinase 2

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

In the current period, we have collaborated with the laboratory of Ping Zhang at NCI to look at how LRRK2 interacts with 14-3-3 proteins. It has been known for a number of years that LRRK2, but not the related protein LRRK1, binds to 14-3-3 via a series of phosphorylated serine residues including Ser 910 and Ser 935. Resolution of the structure using cry-electron microscopy shows that the 14-3-3 bound form of LRRK2 is inactive, with the implication that the enzyme is generally restrained from activity in cells. We were able to test these predictions in cells and also show that mutations in the GTP-binding region of LRRK2 have higher kinase activity, lower binding to 14-3-3 and are less susceptible to inactivation by 14-3-3 portions.