TY - JOUR
T1 - Homo- and heterodimerization of ROCO kinases
T2 - LRRK2 kinase inhibition by the LRRK2 ROCO fragment
AU - Klein, Christian L.
AU - Rovelli, Giorgio
AU - Springer, Wolfdieter
AU - Schall, Christoph
AU - Gasser, Thomas
AU - Kahle, Philipp J.
PY - 2009/11
Y1 - 2009/11
N2 - Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common cause of autosomal-dominant familial and late-onset sporadic Parkinson's disease (PD). LRRK2 is a large multi-domain protein featuring a GTP-binding C-terminal of Ras of complex proteins (ROC) (ROCO) domain combination unique for the ROCO protein family, directly followed by a kinase domain. Dimerization is a well-established phenomenon among protein kinases. Here, we confirm LRRK2 self-interaction, and provide evidence for general homo- and heterodimerization potential among the ROCO kinase family (LRRK2, LRRK1, and death-associated protein kinase 1). The ROCO domain was critically, though not exclusively involved in dimerization, as a LRRK2 deletion mutant lacking the ROCO domain retained dimeric properties. GTP binding did not appear to influence ROCOLRRK2 self-interaction. Interestingly, ROCOLRRK2 fragments exerted an inhibitory effect on both wild-type and the elevated G2019S LRRK2 autophosphorylation activity. Insertion of PD mutations into ROCO LRRK2 reduced self-interaction and led to a reduction of LRRK2 kinase inhibition. Collectively, these results suggest a functional link between ROCO interactions and kinase activity of wild-type and mutant LRRK2. Importantly, our finding of ROCOLRRK2 fragment-mediated LRRK2 kinase inhibition offers a novel lead for drug design and thus might have important implications for new therapeutic avenues in PD.
AB - Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common cause of autosomal-dominant familial and late-onset sporadic Parkinson's disease (PD). LRRK2 is a large multi-domain protein featuring a GTP-binding C-terminal of Ras of complex proteins (ROC) (ROCO) domain combination unique for the ROCO protein family, directly followed by a kinase domain. Dimerization is a well-established phenomenon among protein kinases. Here, we confirm LRRK2 self-interaction, and provide evidence for general homo- and heterodimerization potential among the ROCO kinase family (LRRK2, LRRK1, and death-associated protein kinase 1). The ROCO domain was critically, though not exclusively involved in dimerization, as a LRRK2 deletion mutant lacking the ROCO domain retained dimeric properties. GTP binding did not appear to influence ROCOLRRK2 self-interaction. Interestingly, ROCOLRRK2 fragments exerted an inhibitory effect on both wild-type and the elevated G2019S LRRK2 autophosphorylation activity. Insertion of PD mutations into ROCO LRRK2 reduced self-interaction and led to a reduction of LRRK2 kinase inhibition. Collectively, these results suggest a functional link between ROCO interactions and kinase activity of wild-type and mutant LRRK2. Importantly, our finding of ROCOLRRK2 fragment-mediated LRRK2 kinase inhibition offers a novel lead for drug design and thus might have important implications for new therapeutic avenues in PD.
KW - Death-associated protein kinase 1
KW - Dimerization
KW - Kinase inhibition
KW - Leucine-rich repeat kinase 1
KW - Leucine-rich repeat kinase 2
KW - Parkinson's disease
UR - http://www.scopus.com/inward/record.url?scp=70349929185&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70349929185&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2009.06358.x
DO - 10.1111/j.1471-4159.2009.06358.x
M3 - Article
C2 - 19712061
AN - SCOPUS:70349929185
SN - 0022-3042
VL - 111
SP - 703
EP - 715
JO - Journal of neurochemistry
JF - Journal of neurochemistry
IS - 3
ER -