Roc, the G-domain of the Parkinson's disease-associated protein LRRK2

Abstract

Mutation in leucine-rich repeat (LRR) kinase 2 (LRRK2) is a common cause of Parkinson's disease (PD). Aberrant LRRK2 kinase activity is associated with disease pathogenesis and thus it is an attractive drug target for combating PD. Intense efforts in the past nearly two decades have focused on the development of small-molecule inhibitors of the kinase domain of LRRK2 and have identified potent kinase inhibitors. However, most LRRK2 kinase inhibitors have shown adverse effects; therefore, alternative-mechanism-based strategies are desperately needed. In this review, we discuss the new insights gleaned from recent cryoelectron microscope (cryo-EM) structures of LRRK2 towards understanding the mechanisms of actions of LRRK2 and explore the potential new therapeutic avenues.

Keywords: COR; GTPase; Roc; allosteric regulation; kinase; therapeutics.

Figure 1.. Structure of LRRK2.

a) The primary structure of LRRK2 consists of 2527 amino acids folded into seven domains, including Armadillo (ARM), Ankyrin (ANK), Ras of complex proteins (Roc), C-terminal of Roc (COR), kinase (Kinase), and WD40. b) Ribbon presentation of LRRK2 showing the Roc domain (yellow) cradled in the center of the COR domain (orange). The ANK domain (purple) and LRR domain (blue) wrap around the Kin domain (red). The WD40 domain (green) tethers the kinase domain via a long C-terminal helix. This conformation is believed to be a kinase-inactive state. (PDB ID: 7LI4)

Figure 2.. Potential allosteric regulation of kinase activity.

a) Ribbon representation showing the Roc-COR tandem domain (yellow-orange) is mostly separated from the Kin domain in a kinase-inactive conformation (PDB ID: 7LI4). b) A theoretic model of Roc allosterically modulates the kinase of LRRK2 constructed by manually rotating Roc of PDB ID 7LI4 closer to its kinase domain based on recent structural data [38]. The Roc-COR tandem domain has rotated closer to and interacts directly with the Kin domain in a kinase-active conformation. This movement might be regulated by a rotation of Roc relative to COR by about 15 degrees [38].

Figure 3.. The Roc-COR interface.

Semi-transparent surface rendering of the Roc-COR domain of LRRK2 (yellow-orange) showing the Switch II (blue) is buried deep in the center of the interface cleft of COR. Both PD-mutations in Roc and in COR reside at the interface between the two domains. (PDB ID: 7LI4)

Figure 4.

A theoretical model of GDP-GTP-dependent conformational change in Roc leading to a global structural change in LRRK2. The nucleotide-dependent conformational changes in Roc-COR, in addition to modulating the kinase activity of LRRK2 by the direct interaction between COR and kinase domain as described in [38] and depicted in Figure 2 above, potentially leads to a broad global conformational change and modulate the other activities of LRRK2, such as substrate binding and subcellular localization.