GTP Binding Is Essential to the Protein Kinase Activity of LRRK2, a Causative Gene Product for Familial Parkinson's Disease†

Biochemistry ◽  
2007 ◽  
Vol 46 (5) ◽  
pp. 1380-1388 ◽  
Author(s):  
Genta Ito ◽  
Takuro Okai ◽  
Go Fujino ◽  
Kohsuke Takeda ◽  
Hidenori Ichijo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Kinase ◽  
Gene Product ◽  
Kinase Activity ◽  
Protein Kinase Activity ◽  
Causative Gene ◽  
Gtp Binding ◽  
Familial Parkinson’S Disease

scholarly journals A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels

2021 ◽  
Vol 22 (7) ◽  
pp. 3708
Author(s):  
Jun Ogata ◽  
Kentaro Hirao ◽  
Kenya Nishioka ◽  
Arisa Hayashida ◽  
Yuanzhe Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Peripheral Blood ◽  
Kinase Activity ◽  
Late Onset ◽  
Causative Gene ◽  
Protein Levels ◽  
Wd40 Domain ◽  
Lrrk2 Protein ◽  
Familial Parkinson’S Disease

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.

scholarly journals 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization

2010 ◽  
Vol 430 (3) ◽  
pp. 393-404 ◽  
Author(s):  
R. Jeremy Nichols ◽  
Nicolas Dzamko ◽  
Nicholas A. Morrice ◽  
David G. Campbell ◽  
Maria Deak ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Kinase ◽  
Inclusion Bodies ◽  
Kinase Activity ◽  
Protein Isoforms ◽  
Protein Kinase Activity ◽  
Leucine Rich Repeat ◽  
Pathogenic Mutations ◽  
Mouse Tissues

LRRK2 (leucine-rich repeat protein kinase 2) is mutated in a significant number of Parkinson's disease patients, but still little is understood about how it is regulated or functions. In the present study we have demonstrated that 14-3-3 protein isoforms interact with LRRK2. Consistent with this, endogenous LRRK2 isolated from Swiss 3T3 cells or various mouse tissues is associated with endogenous 14-3-3 isoforms. We have established that 14-3-3 binding is mediated by phosphorylation of LRRK2 at two conserved residues (Ser910 and Ser935) located before the leucine-rich repeat domain. Our results suggests that mutation of Ser910 and/or Ser935 to disrupt 14-3-3 binding does not affect intrinsic protein kinase activity, but induces LRRK2 to accumulate within discrete cytoplasmic pools, perhaps resembling inclusion bodies. To investigate links between 14-3-3 binding and Parkinson's disease, we studied how 41 reported mutations of LRRK2 affected 14-3-3 binding and cellular localization. Strikingly, we found that five of the six most common pathogenic mutations (R1441C, R1441G, R1441H, Y1699C and I2020T) display markedly reduced phosphorylation of Ser910/Ser935 thereby disrupting interaction with 14-3-3. We have also demonstrated that Ser910/Ser935 phosphorylation and 14-3-3 binding to endogenous LRRK2 is significantly reduced in tissues of homozygous LRRK2(R1441C) knock-in mice. Consistent with 14-3-3 regulating localization, all of the common pathogenic mutations displaying reduced 14-3-3-binding accumulated within inclusion bodies. We also found that three of the 41 LRRK2 mutations analysed displayed elevated protein kinase activity (R1728H, ~2-fold; G2019S, ~3-fold; and T2031S, ~4-fold). These results provide the first evidence suggesting that 14-3-3 regulates LRRK2 and that disruption of the interaction of LRRK2 with 14-3-3 may be linked to Parkinson's disease.

scholarly journals Cell surface expression of v-fms-coded glycoproteins is required for transformation.

1984 ◽  
Vol 4 (10) ◽  
pp. 1999-2009 ◽  
Author(s):  
M F Roussel ◽  
C W Rettenmier ◽  
A T Look ◽  
C J Sherr
Keyword(s):  
Amino Acids ◽  
Protein Kinase ◽  
Cell Surface ◽  
Gene Product ◽  
Kinase Activity ◽  
Specific Protein ◽  
Protein Kinase Activity ◽  
Wild Type ◽  
Specific Protein Kinase

The viral oncogene v-fms encodes a transforming glycoprotein with in vitro tyrosine-specific protein kinase activity. Although most v-fms-coded molecules remain internally sequestered in transformed cells, a minor population of molecules is transported to the cell surface. An engineered deletion mutant lacking 348 base pairs of the 3.0-kilobase-pair v-fms gene encoded a polypeptide that was 15 kilodaltons smaller than the wild-type v-fms gene product. The in-frame deletion of 116 amino acids was adjacent to the transmembrane anchor peptide located near the middle of the predicted protein sequence and 432 amino acids from the carboxyl terminus. The mutant polypeptide acquired N-linked oligosaccharide chains, was proteolytically processed in a manner similar to the wild-type glycoprotein, and exhibited an associated tyrosine-specific protein kinase activity in vitro. However, the N-linked oligosaccharides of the mutant glycoprotein were not processed to complex carbohydrate chains, and the glycoprotein was not detected at the cell surface. Cells expressing high levels of the mutant glycoprotein did not undergo morphological transformation and did not form colonies in semisolid medium. The transforming activity of the v-fms gene product therefore appears to be mediated through target molecules on the plasma membrane.

scholarly journals Protein Kinase Activity Associated with theIME2 Gene Product, a Meiotic Inducer in the YeastSaccharomyces cerevisiae

1993 ◽  
Vol 57 (10) ◽  
pp. 1731-1735 ◽  
Author(s):  
Kin-ichiro Kominami ◽  
Yushi Sakata ◽  
Masami Sakai ◽  
Ichiro Yamashita
Keyword(s):  
Protein Kinase ◽  
Gene Product ◽  
Kinase Activity ◽  
Protein Kinase Activity

scholarly journals Characterization of the protein kinase activity of avian sarcoma virus src gene product.

1979 ◽  
Vol 76 (10) ◽  
pp. 5028-5032 ◽  
Author(s):  
P. F. Maness ◽  
H. Engeser ◽  
M. E. Greenberg ◽  
M. O'Farrell ◽  
W. E. Gall ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Gene Product ◽  
Kinase Activity ◽  
Protein Kinase Activity ◽  
Avian Sarcoma Virus ◽  
Src Gene ◽  
Sarcoma Virus ◽  
Avian Sarcoma

Cell surface expression of v-fms-coded glycoproteins is required for transformation

1984 ◽  
Vol 4 (10) ◽  
pp. 1999-2009
Author(s):  
M F Roussel ◽  
C W Rettenmier ◽  
A T Look ◽  
C J Sherr
Keyword(s):  
Amino Acids ◽  
Protein Kinase ◽  
Cell Surface ◽  
Gene Product ◽  
Kinase Activity ◽  
Specific Protein ◽  
Protein Kinase Activity ◽  
Wild Type ◽  
Specific Protein Kinase

The viral oncogene v-fms encodes a transforming glycoprotein with in vitro tyrosine-specific protein kinase activity. Although most v-fms-coded molecules remain internally sequestered in transformed cells, a minor population of molecules is transported to the cell surface. An engineered deletion mutant lacking 348 base pairs of the 3.0-kilobase-pair v-fms gene encoded a polypeptide that was 15 kilodaltons smaller than the wild-type v-fms gene product. The in-frame deletion of 116 amino acids was adjacent to the transmembrane anchor peptide located near the middle of the predicted protein sequence and 432 amino acids from the carboxyl terminus. The mutant polypeptide acquired N-linked oligosaccharide chains, was proteolytically processed in a manner similar to the wild-type glycoprotein, and exhibited an associated tyrosine-specific protein kinase activity in vitro. However, the N-linked oligosaccharides of the mutant glycoprotein were not processed to complex carbohydrate chains, and the glycoprotein was not detected at the cell surface. Cells expressing high levels of the mutant glycoprotein did not undergo morphological transformation and did not form colonies in semisolid medium. The transforming activity of the v-fms gene product therefore appears to be mediated through target molecules on the plasma membrane.

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