Structure of the Roc–COR domain tandem of C. tepidum, a prokaryotic homologue of the human LRRK2 Parkinson kinase

Gotthardt, Katja; Weyand, Michael; Kortholt, Arjan; Haastert, Peter J.M. van; Wittinghofer, Alfred

doi:10.1038/emboj.2008.167

Cited by 43 publications

(80 citation statements)

References 33 publications

(48 reference statements)

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“…The structure of a bacterial homolog shows that Roc is a bona fide Ras G domain and that the RocCOR tandem appears to act as a GAD device (119). The domain swapping found in crystals of the human Roc domain of LRRK2 has been considered an artifact of the crystallization procedure (119). Biochemical experiments in solution confirmed that domain swapping observed for the G domain of Rab27 was indeed a crystallographic artifact (120).…”

Section: Trme/era/enga/yiha/septin-like Superfamilymentioning

confidence: 90%

“…Roco proteins contain a tandem arrangement of Roc (Ras of complex proteins) and COR (C-terminal of Ras) domains also found in the human protein LRRK2 (leucinerich-repeat kinase) mutated in patients with Parkinson's (118). The structure of a bacterial homolog shows that Roc is a bona fide Ras G domain and that the RocCOR tandem appears to act as a GAD device (119). The domain swapping found in crystals of the human Roc domain of LRRK2 has been considered an artifact of the crystallization procedure (119).…”

Section: Trme/era/enga/yiha/septin-like Superfamilymentioning

confidence: 98%

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Structure-Function Relationships of the G Domain, a Canonical Switch Motif

Wittinghofer

Vetter

2011

Annu. Rev. Biochem.

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GTP-binding (G) proteins constitute a class of P-loop (phosphate-binding loop) proteins that work as molecular switches between the GDP-bound OFF and the GTP-bound ON state. The common principle is the 160-180-residue G domain with an α,β topology that is responsible for nucleotide-dependent conformational changes and drives many biological functions. Although the G domain uses a universally conserved switching mechanism, its structure, function, and GTPase reaction are modified for many different pathways and processes.

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Section: Trme/era/enga/yiha/septin-like Superfamilymentioning

confidence: 90%

Section: Trme/era/enga/yiha/septin-like Superfamilymentioning

confidence: 98%

Structure-Function Relationships of the G Domain, a Canonical Switch Motif

Wittinghofer

Vetter

2011

Annu. Rev. Biochem.

Self Cite

401

438

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“…Crystal structures of the roc domain of LRRK2 and the Roc-COR domain of a prokaryotic Roco protein have been solved recently. 39,40 To get information about the spatial localization of the bona fide autophosphorylation residues, we mapped the identified sites to the Roc structure 2ZEJ. 39 As shown in Figure 4, LRRK2 autophosphorylation sites cluster around the GTPase binding pocket as well as a previously identified hotspot for LRRK2 pathogenic mutations in residue R1441.…”

Section: Mapping Of Lrrk2 Phosphorylation Sites Reveals Clustering Inmentioning

confidence: 99%

Phosphopeptide Analysis Reveals Two Discrete Clusters of Phosphorylation in the N-Terminus and the Roc Domain of the Parkinson-Disease Associated Protein Kinase LRRK2

et al. 2010

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Mutations in leucine-rich repeat kinase 2 (LRRK2) that increase its kinase activity associate with familial forms of Parkinson disease (PD). As phosphorylation determines the functional state of most protein kinases, we systematically mapped LRRK2 phosphorylation sites by mass spectrometry. Our analysis revealed a high degree of constitutive phosphorylation in a narrow serine-rich region preceding the LRR-domain. Allowing de novo autophosphorylation of purified LRRK2 in an in vitro autokinase assay prior to mass spectrometric analysis, we discovered multiple sites of autophosphorylation. Solely serine and threonine residues were found phosphorylated suggesting LRRK2 as a true serine threonine kinase. Autophosphorylation mainly targets the ROC GTPase domain and its clustering around the GTP binding pocket of ROC suggests cross-regulatory activity between kinase and Roc domain. In conclusion, the phosphoprotein LRRK2 functions as an autocatalytically active serine threonine kinase. Clustering of phosphosites within two discrete domains suggest that phosphorylation may regulate its biological functions in a yet unknown fashion.

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“…While specific mutations can destabilize LRRK2 fragment dimers (Deng et al, 2008; Gotthardt et al, 2008), the extent to which full length LRRK2 dimerization is affected in PD is unclear. How perturbed dimerization may affect LRRK2 function is similarly uncertain, but hypotheses exist.…”

Section: Gene and Protein Organizationmentioning

confidence: 99%

LRRK2, a puzzling protein: Insights into Parkinson's disease pathogenesis

Esteves

Swerdlow

Cardoso

2014

Experimental Neurology

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Leucine-rich repeat kinase 2 (LRRK2) is a large, ubiquitous protein of unknown function. Mutations in the gene encoding LRRK2 have been linked to familial and sporadic Parkinson disease (PD) cases. The LRRK2 protein is a single polypeptide that displays GTPase and kinase activity. Kinase and GTPase domains are involved in different cellular signalling pathways. Despite several experimental studies associating LRRK2 protein with various intracellular membranes and vesicular structures such as endosomal/lysosomal compartments, the mitochondrial outer membrane, lipid rafts, microtubule-associated vesicles, the golgi complex, and the endoplasmic reticulum its broader physiologic function(s) remain unidentified. Additionally, the cellular distribution of LRRK2 may indicate its role in several different pathways, such as the ubiquitin-proteasome system, the autophagic-lysosomal pathway, intracellular trafficking, and mitochondrial dysfunction. This review discusses potential mechanisms through which LRRK2 may mediate neurodegeneration and cause PD.

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Structure of the Roc–COR domain tandem of C. tepidum, a prokaryotic homologue of the human LRRK2 Parkinson kinase

Cited by 43 publications

References 33 publications

Structure-Function Relationships of the G Domain, a Canonical Switch Motif

Structure-Function Relationships of the G Domain, a Canonical Switch Motif

Phosphopeptide Analysis Reveals Two Discrete Clusters of Phosphorylation in the N-Terminus and the Roc Domain of the Parkinson-Disease Associated Protein Kinase LRRK2

LRRK2, a puzzling protein: Insights into Parkinson's disease pathogenesis

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