Homo- and heterodimerization of ROCO kinases

LRRK2 kinase inhibition by the LRRK2 ROCO fragment

Christian L. Klein, Giorgio Rovelli, Wolfdieter Springer, Christoph Schall, Thomas Gasser, Philipp J. Kahle

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)703-715
Number of pages13
JournalJournal of Neurochemistry
Volume111
Issue number3
DOIs
StatePublished - Nov 2009
Externally publishedYes

Fingerprint

Hominidae
Leucine
Phosphotransferases
Parkinson Disease
Dimerization
Guanosine Triphosphate
Death-Associated Protein Kinases
ras Proteins
Mutation
Proteins
Gene encoding
Drug Design
Protein Kinases

Keywords

  • Death-associated protein kinase 1
  • Dimerization
  • Kinase inhibition
  • Leucine-rich repeat kinase 1
  • Leucine-rich repeat kinase 2
  • Parkinson's disease

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Homo- and heterodimerization of ROCO kinases : LRRK2 kinase inhibition by the LRRK2 ROCO fragment. / Klein, Christian L.; Rovelli, Giorgio; Springer, Wolfdieter; Schall, Christoph; Gasser, Thomas; Kahle, Philipp J.

In: Journal of Neurochemistry, Vol. 111, No. 3, 11.2009, p. 703-715.

Research output: Contribution to journalArticle

Klein, Christian L. ; Rovelli, Giorgio ; Springer, Wolfdieter ; Schall, Christoph ; Gasser, Thomas ; Kahle, Philipp J. / Homo- and heterodimerization of ROCO kinases : LRRK2 kinase inhibition by the LRRK2 ROCO fragment. In: Journal of Neurochemistry. 2009 ; Vol. 111, No. 3. pp. 703-715.
@article{e51a1a0222104db8bbbdac5f708c39ac,
title = "Homo- and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment",
abstract = "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.",
keywords = "Death-associated protein kinase 1, Dimerization, Kinase inhibition, Leucine-rich repeat kinase 1, Leucine-rich repeat kinase 2, Parkinson's disease",
author = "Klein, {Christian L.} and Giorgio Rovelli and Wolfdieter Springer and Christoph Schall and Thomas Gasser and Kahle, {Philipp J.}",
year = "2009",
month = "11",
doi = "10.1111/j.1471-4159.2009.06358.x",
language = "English (US)",
volume = "111",
pages = "703--715",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "3",

}

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

VL - 111

SP - 703

EP - 715

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 3

ER -