LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain

Korr, Daniel; Toschi, Luisella; Donner, Peter; Pohlenz, Hans-Dieter; Kreft, Bertolt; Weiß, Bertram

doi:10.1016/j.cellsig.2005.08.015

Cited by 107 publications

(128 citation statements)

References 32 publications

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“…Therefore, these recent results should be reevaluated, taking this fact into account. In my opinion, all the results in invertebrates and the results obtained for LRRK1 (Korr et al 2006;Greggio et al 2007;Taylor et al 2007) and LRRK2 (summarized in Marín 2006;Thomas and Beal 2007) in vertebrates are compatible with all the LRRK gene products in animals being involved in neuronal functions. This is consistent with their presence only in animals with a developed nervous system, from cnidarians to vertebrates.…”

Section: Discussionsupporting

confidence: 53%

Ancient Origin of the Parkinson Disease Gene LRRK2

Marı́n

2008

J Mol Evol

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Dominant mutations in the LRRK2 gene, a member of the Roco family, cause both familial and sporadic Parkinson disease. LRRK genes had so far been detected only in bilaterian animals. In deuterostomes, including humans, two LRRK genes (LRRK1 and LRRK2) exist, while in protostomes a single LRRK gene has been found. In this study, I combine structural and phylogenetic analyses to show that the cnidarian Nematostella vectensis has four LRRK genes. One of them is a bona fide orthologue of the human LRRK2 gene, demonstrating that this gene has an ancient origin. Two others are, respectively, orthologues of the deuterostome LRRK1 and the protostome LRRK genes. The fourth gene is probably cnidarian-specific. This precise characterization of the early evolution of LRRK genes in animals has important implications, because it indicates that the Drosophila and Caenorhabditis LRRK genes, which are studied to gain an understanding of LRRK2 function, are not true orthologues of the human Parkinson disease gene. Novel functional insights are also gained by comparison of the structures of LRRK2 genes in distantly related species.

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Section: Discussionsupporting

confidence: 53%

Ancient Origin of the Parkinson Disease Gene LRRK2

Marı́n

2008

J Mol Evol

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“…Mutations at position R1441 in LRRK2 (R1441C, R1441G, and R1441H) are all pathogenic for PD (12, 13), and another variant also is reported at the adjacent residue [A1442P (14)] in the ROC domain. Several studies have shown that GTP binding at the ROC domain regulates kinase activity (4,7,10,15,16). In other recent data, ROC domain mutants have been shown to have lower GTPase activity than wild-type LRRK2 (15,17,18), although it is likely that the GTPase activity is quite low as other groups did not find measurable GTPase activity in full-length LRRK2 (11) unless the protein was mutated to residues that are similar to Ras (16).…”

mentioning

confidence: 86%

Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase

Deng

Lewis

Greggio

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

220

280

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Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of Parkinson's disease (PD). LRRK2 contains a Ras of complex proteins (ROC) domain that may act as a GTPase to regulate its protein kinase activity. The structure of ROC and the mechanism(s) by which it regulates kinase activity are not known. Here, we report the crystal structure of the LRRK2 ROC domain in complex with GDP-Mg 2؉ at 2.0-Å resolution. The structure displays a dimeric fold generated by extensive domain-swapping, resulting in a pair of active sites constructed with essential functional groups contributed from both monomers. Two PD-associated pathogenic residues, R1441 and I1371, are located at the interface of two monomers and provide exquisite interactions to stabilize the ROC dimer. The structure demonstrates that loss of stabilizing forces in the ROC dimer is likely related to decreased GTPase activity resulting from mutations at these sites. Our data suggest that the ROC domain may regulate LRRK2 kinase activity as a dimer, possibly via the C-terminal of ROC (COR) domain as a molecular hinge. The structure of the LRRK2 ROC domain also represents a signature from a previously undescribed class of GTPases from complex proteins and results may provide a unique molecular target for therapeutics in PD. Parkinson's disease (PD) is a common, age-related neurodegenerative disorder for which only symptomatic treatment is available. The etiology of PD is poorly understood, but over the past decade it has become clear that there are rare families with Mendelian inheritance (1). Of the genes that cause PD, dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are numerically the most common and account for an appreciable fraction of apparently sporadic PD (reviewed in ref.2). LRRK2 encodes a large (2,527-aa) multidomain protein originally identified as a unique kinase with leucine-rich repeats. LRRK2 is a member of a superfamily of proteins, named ROCO, that includes at least three other human proteins: leucine-rich repeat kinase 1 (LRRK1), death-associated protein kinase (DAPK1), and malignant fibrous histiocytoma-amplified sequences with leucine-rich tandem repeat-1 (MASL1) (3). A unique feature of all ROCO proteins is a 200-to 250-aa Ras-related GTPase or Ras of complex proteins (ROC) domain, followed by a C-terminal of ROC (COR) domain immediately before the kinase domain.Both LRRK2 and LRRK1 have been shown to be active protein kinases in vitro (4-7), and some mutations are found in the kinase domain. These mutations generally increase kinase activity, although there are some discrepancies in different studies as to whether all mutations increase kinase function (4,6,(8)(9)(10)(11). However, the kinase activity of LRRK2 is required for the ability of the mutant protein to cause neuronal damage, at least in cell culture models (5, 10), suggesting that kinase inhibitors may represent a therapeutic avenue for PD.Although the kinase domain therefore is important in understanding pathogenesis, mutations also are fo...

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“…Binding of GTP to the GTPase-like Roc domain leads to the stimulation of LRRK1 kinase activity. 2 Mutation analysis indicated that the COR domain might be important for transmitting the stimulating signal to the KD. 2 The function of RIP6 and RIP7 is yet unknown; however, mutations in the human LRRK2 gene are associated with both familial and sporadic Parkinson's disease.…”

mentioning

confidence: 99%

“…2 Mutation analysis indicated that the COR domain might be important for transmitting the stimulating signal to the KD. 2 The function of RIP6 and RIP7 is yet unknown; however, mutations in the human LRRK2 gene are associated with both familial and sporadic Parkinson's disease. 3 RIP1, the first member of the family, was discovered more than 10 years ago.…”

mentioning

confidence: 99%

RIP1, a kinase on the crossroads of a cell's decision to live or die

et al. 2007

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Binding of inflammatory cytokines to their receptors, stimulation of pathogen recognition receptors by pathogen-associated molecular patterns, and DNA damage induce specific signalling events. A cell that is exposed to these signals can respond by activation of NF-jB, mitogen-activated protein kinases and interferon regulatory factors, resulting in the upregulation of antiapoptotic proteins and of several cytokines. The consequent survival may or may not be accompanied by an inflammatory response. Alternatively, a cell can also activate death-signalling pathways, resulting in apoptosis or alternative cell death such as necrosis or autophagic cell death. Interplay between survival and death-promoting complexes continues as they compete with each other until one eventually dominates and determines the cell's fate. RIP1 is a crucial adaptor kinase on the crossroad of these stress-induced signalling pathways and a cell's decision to live or die. Following different upstream signals, particular RIP1-containing complexes are formed; these initiate only a limited number of cellular responses. In this review, we describe how RIP1 acts as a key integrator of signalling pathways initiated by stimulation of death receptors, bacterial or viral infection, genotoxic stress and T-cell homeostasis. Cell Death and Differentiation (2007) 14, 400-410. doi:10.1038/sj.cdd.4402085Receptor interacting protein (RIP) kinases constitute a family of seven members, all of which contain a kinase domain (KD) (Figure 1a). They are crucial regulators of cell survival and death 1 (Figure 2). Based on sequence similarities, mode of regulation and substrate specificities of their catalytic domain, RIP kinases are classified as serine/threonine kinases and are closely related to members of the interleukin-1-receptorassociated kinase (IRAK) family. RIP1 and RIP2 (CARDIAK/ RICK) also bear a C-terminal domain belonging to the death domain (DD) superfamily, namely, a DD and a caspase recruitment domain (CARD), respectively, allowing recruitment to large protein complexes initiating different signalling pathways. The unique C-terminus of RIP3 bears a RIP homotypic interaction motif (RHIM), which is also present in the intermediate domain (ID) of RIP1. This RHIM domain is sufficient for interaction of RIP1 with RIP3. 1 RIP4 (DIK/PKK) and RIP5 (SgK288) are characterized by the presence of ankyrin repeats in their C-terminal domains. 1 RIP6 (LRRK1) and RIP7 (LRRK2) are RIP members containing a leucine-rich repeat (LRR) motif 1 that may be involved in recognition of pathogen-, damage-or stress-associated molecular patterns (PAMP, DAMP, SAMP). In addition, they harbor Roc/COR domains (Ras of complex proteins/C-terminal of Roc). Binding of GTP to the GTPase-like Roc domain leads to the stimulation of LRRK1 kinase activity. 2 Mutation analysis indicated that the COR domain might be important for transmitting the stimulating signal to the KD. 2 The function of RIP6 and RIP7 is yet unknown; however, mutations in the human LRRK2 gene are associated with both fam...

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LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain

Cited by 107 publications

References 32 publications

Ancient Origin of the Parkinson Disease Gene LRRK2

Ancient Origin of the Parkinson Disease Gene LRRK2

Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase

RIP1, a kinase on the crossroads of a cell's decision to live or die

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