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Structural biology of the LRRK2 GTPase and kinase domains: implications for regulation.

Gilsbach BK, Kortholt A - Front Mol Neurosci (2014)

Bottom Line: Several of the pathogenic mutations in LRRK2 result in decreased GTPase activity and enhanced kinase activity, suggesting a possible PD-related gain of abnormal function.Studies with Roco proteins from the model organism Dictyostelium discoideum revealed that PD mutants have different effects and most importantly they explained the G2019S-related increased LRRK2 kinase activity.In this review we highlight the recent progress in structural and biochemical characterization of Roco proteins and discuss its implication for the understanding of the complex regulatory mechanism of LRRK2.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biochemistry, University of Groningen Groningen, Netherlands.

ABSTRACT
Human leucine rich repeat kinase 2 (LRRK2) belongs to the Roco family of proteins, which are characterized by the presence of a Ras-like G-domain (Roc), a C-terminal of Roc domain (COR), and a kinase domain. Mutations in LRRK2 have been found to be thus far the most frequent cause of late-onset Parkinson's disease (PD). Several of the pathogenic mutations in LRRK2 result in decreased GTPase activity and enhanced kinase activity, suggesting a possible PD-related gain of abnormal function. Important progress in the structural understanding of LRRK2 has come from our work with related Roco proteins from lower organisms. Atomic structures of Roco proteins from prokaryotes revealed that Roco proteins belong to the GAD class of molecular switches (G proteins activated by nucleotide dependent dimerization). As in LRRK2, PD-analogous mutations in Roco proteins from bacteria decrease the GTPase reaction. Studies with Roco proteins from the model organism Dictyostelium discoideum revealed that PD mutants have different effects and most importantly they explained the G2019S-related increased LRRK2 kinase activity. Furthermore, the structure of Dictyostelium Roco4 kinase in complex with the LRRK2 inhibitor H1152 showed that Roco4 and other Roco family proteins can be important for the optimization of the current, and identification of new, LRRK2 kinase inhibitors. In this review we highlight the recent progress in structural and biochemical characterization of Roco proteins and discuss its implication for the understanding of the complex regulatory mechanism of LRRK2.

No MeSH data available.


Related in: MedlinePlus

Working model for the complex LRRK2 activation mechanism.
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Figure 4: Working model for the complex LRRK2 activation mechanism.

Mentions: Altogether, the structural and biochemical data suggest that LRRK2 activity is regulated by at least two different mechanisms: intramolecular activation and binding of input/substrate to the N- and C- terminal domains (Figure 4). The COR domain functions as a dimerization device. Within the dimer, the Roco G-domains are flexible in the GDP-bound inactive state, but in the active form the G-domains come in a more fixed state in close proximity to each other. This conformational change is transmitted to other parts of the protein, which subsequently allows the activation loops of the two kinase protomers to be autophosphorylated and activated. The GTPase reaction is also critically dependent on dimerization, because efficient catalytic machinery is formed by complementation of the active site of one protomer with that of the other protomer. In this way the intramolecular GTPase reaction functions as a timing device for the activation and biological function of Roco proteins. The N- and C-terminal segments of LRRK2 regulate this intramolecular signaling cascade and are important for kinase activity, oligomerization, and/or localization. Most likely the N- and C-terminal protein-protein interaction domains are directly binding upstream proteins and/or downstream effector proteins and thereby determine the specificity of the Roco proteins.


Structural biology of the LRRK2 GTPase and kinase domains: implications for regulation.

Gilsbach BK, Kortholt A - Front Mol Neurosci (2014)

Working model for the complex LRRK2 activation mechanism.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4017136&req=5

Figure 4: Working model for the complex LRRK2 activation mechanism.
Mentions: Altogether, the structural and biochemical data suggest that LRRK2 activity is regulated by at least two different mechanisms: intramolecular activation and binding of input/substrate to the N- and C- terminal domains (Figure 4). The COR domain functions as a dimerization device. Within the dimer, the Roco G-domains are flexible in the GDP-bound inactive state, but in the active form the G-domains come in a more fixed state in close proximity to each other. This conformational change is transmitted to other parts of the protein, which subsequently allows the activation loops of the two kinase protomers to be autophosphorylated and activated. The GTPase reaction is also critically dependent on dimerization, because efficient catalytic machinery is formed by complementation of the active site of one protomer with that of the other protomer. In this way the intramolecular GTPase reaction functions as a timing device for the activation and biological function of Roco proteins. The N- and C-terminal segments of LRRK2 regulate this intramolecular signaling cascade and are important for kinase activity, oligomerization, and/or localization. Most likely the N- and C-terminal protein-protein interaction domains are directly binding upstream proteins and/or downstream effector proteins and thereby determine the specificity of the Roco proteins.

Bottom Line: Several of the pathogenic mutations in LRRK2 result in decreased GTPase activity and enhanced kinase activity, suggesting a possible PD-related gain of abnormal function.Studies with Roco proteins from the model organism Dictyostelium discoideum revealed that PD mutants have different effects and most importantly they explained the G2019S-related increased LRRK2 kinase activity.In this review we highlight the recent progress in structural and biochemical characterization of Roco proteins and discuss its implication for the understanding of the complex regulatory mechanism of LRRK2.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biochemistry, University of Groningen Groningen, Netherlands.

ABSTRACT
Human leucine rich repeat kinase 2 (LRRK2) belongs to the Roco family of proteins, which are characterized by the presence of a Ras-like G-domain (Roc), a C-terminal of Roc domain (COR), and a kinase domain. Mutations in LRRK2 have been found to be thus far the most frequent cause of late-onset Parkinson's disease (PD). Several of the pathogenic mutations in LRRK2 result in decreased GTPase activity and enhanced kinase activity, suggesting a possible PD-related gain of abnormal function. Important progress in the structural understanding of LRRK2 has come from our work with related Roco proteins from lower organisms. Atomic structures of Roco proteins from prokaryotes revealed that Roco proteins belong to the GAD class of molecular switches (G proteins activated by nucleotide dependent dimerization). As in LRRK2, PD-analogous mutations in Roco proteins from bacteria decrease the GTPase reaction. Studies with Roco proteins from the model organism Dictyostelium discoideum revealed that PD mutants have different effects and most importantly they explained the G2019S-related increased LRRK2 kinase activity. Furthermore, the structure of Dictyostelium Roco4 kinase in complex with the LRRK2 inhibitor H1152 showed that Roco4 and other Roco family proteins can be important for the optimization of the current, and identification of new, LRRK2 kinase inhibitors. In this review we highlight the recent progress in structural and biochemical characterization of Roco proteins and discuss its implication for the understanding of the complex regulatory mechanism of LRRK2.

No MeSH data available.


Related in: MedlinePlus