Brahma, Musukha Mala and Misra, Ashish
(2018)
CONSTRUCTION OF LANDSCAPE OF DISEASE CAUSING MUTATION IN NEURODEGENERATIVE DISEASE
AND
DOCKING STUDIES TO IDENTIFY INHIBITORS TO PREVENT GTP BINDING AND INCREASE IN KINASE ACTIVITY.
Masters thesis, Indian Institute of Technology Hyderabad.
Abstract
Leucine-rich repeat kinase 2(LRRK2) is the greatest known genetic contributor to Parkinson's disease (PD). LRRK2 encodes a 2527 amino-acid multi-domain protein. It has several regions predicted to be involved in protein-protein interactions, which include an ankyrin repeat domain, a leucine-rich repeat domain and a WD40 domain. It also has two catalytic domains including a kinase domain of the tyrosine kinase-like family and a GTPase domain of the Ras of complex proteins family (ROC). Tyrosine kinase and Ras family GTPases like kinases are often associated as elements of the same intracellular signalling pathway, that suggest a functional interaction between both of these catalytic functions within LRRK2. Roc GTPase domain represents hotspot for mutations it has three PD mutations at a single R1441 residue (i.e., R1441C, R1441G, and R1441H), two PD mutations at a single T1343 residue (i.e., T1343G and T1343V), N1437H, I1371V, K1347A, R1398H, and T1348N. Y1699C mutation is the only known disease-causing variant in COR domain. G2019S and I2020T, located in adjacent residues of the kinase activation loop, are known to cause familial PD. Mutation in LRRK2 causes impairment in GTPase activity and therefore alters kinase activity. Kinase activity of LRRK2 requires an intact of ROC and GTPase domain. The activity of LRRK2 kinase increases when GTP binds to the GTPase (ROC) domain. The increase in Kinase activity on GTP binding is the cause of PD as known for now. There is a number of mutations in the domains present in LRRK2 that is responsible for changes in GTPase activity and Kinase activity. Mutations in the catalytic ROC-COR and kinase domains of LRRK2 are considered as the most common causes of PD. Mutations located in the kinase domain influence only kinase activity whereas mutations in ROC domain may influence both GTP-binding and kinase activity. The GTPase domain plays a role in regulating kinase activity, and in mediating the neurotoxic effects of LRRK2. Therefore, the GTPase domain and Kinase domain is studied as a therapeutic target for inhibiting the pathogenic effects of LRRK2 mutations. LRRK2 Roc domain structure from UniProt: Q5S007 (LRRK2_HUMAN) and Homology modelling of Kinase domain are done in Swiss-Model to study the inhibition efficiency of GTP binding and Kinase activity.
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