Targeting Post-translational Modification

targeting kinase activity
Post-Translational Modification, Targeting Dysfunction in Protein Biology, PARK2 (Parkin), PARK6 (PINK1), PARK8 (LRRK2)

Protein kinases are essential players in cellular signal cascades and have very diverse roles in numerous signaling pathways that regulate a wide variety of cellular functions. This diversity, as well as the mechanics of their function, makes kinases attractive targets for drug design.

Due to the identification of mutations in LRRK2 in PD patients, novel therapeutic approaches are being developed to target the kinase activity of this protein. However, it has not been definitively determined that LRRK2 kinase activity is the appropriate target for disease-modifying therapies.

Mutation to PINK1 is associated with PD, observed in both familial and sporadic PD. Mutations are thought to induce a loss-of-function in the kinase activity of PINK1. There is also interest in investigating phosphorylation of alpha-synuclein as a therapeutic target.

Contributions:
The substrate hunt continues...
Which LRRK2 kinase substrates identified to date are most likely to be true physiological substrates? What limitations/barriers hinder identification of novel substrates?
Holli Kawadler, MJFF
25 Jan 2010
A recent publication from Mark Cookson's group suggests that 4E-BP is likely not a direct substrate for LRRK2 kinase activity, following up on initial studies by Imai et al. (2008). They confirmed ... 
Independent datasets that agree with each other...LRRK2 autophosphorylation in ROC
Which LRRK2 kinase substrates identified to date are most likely to be true physiological substrates? What limitations/barriers hinder identification of novel substrates?
Mark Cookson, NIH
15 Oct 2009
Brief update; the Iwatsubo group in Tokyo has just published a paper in Biochemistry identifying four sites in the ROC domain that overlap with our own analyses: Ser1403, Thr1404, Thr1410 and ... 
The Utility of a LRRK2 Dimer
Which LRRK2 kinase substrates identified to date are most likely to be true physiological substrates? What limitations/barriers hinder identification of novel substrates?
Andrew B West, UAB
14 Oct 2009
In 2007, our group and others began developing ways to visualize LRRK2 conformations using native PAGE and gel filtrations, and found that a proportion of LRRK2 protein is present as dimer-sized ... 
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Research Questions:
What is the relationship between LRRK2 and synuclein? And Tau?
12 Feb 2010
Mutations in the gene coding for the putative kinase LRRK2 represent some of the most prevalent genetic factors yet linked to Parkinson’s disease, but how these alterations lead to PD-related ... 
Responses: 4
Which LRRK2 kinase substrates identified to date are most likely to be true physiological substrates? What limitations/barriers hinder identification of novel substrates?
25 Jan 2010
Mutations in the gene coding for the putative kinase LRRK2 represent some of the most prevalent genetic factors yet linked to Parkinson’s disease, but how these alterations lead to PD-related ... 
Responses: 9
What do we know about the function of LRRK2 in cellular processes that may shed light on its role in PD pathogenesis? Is LRRK2 kinase activity key to this regulation or do other features/functions of LRRK2 contribute?
01 Oct 2009
Mutations in the gene coding for the putative kinase LRRK2 represent some of the most prevalent genetic factors yet linked to Parkinson's disease, but how these alterations lead to PD-related ... 
Responses: 3
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Workgroups:
LRRK2 substrate workgroup
13 Feb 2009
Mutations within PARK8 (LRRK2/dardarin) are associated with autosomal dominant familial PD. LRRK2 contains multiple protein-binding domains and catalytic domains, including a Roc-GTPase domain and a ...