Identification of leucine-rich repeat receptor-like protein kinase (LRR-RLK) genes in paper mulberry and their potential roles in response to cold stress

DAPK (death-associated protein kinase) is a newly recognized member of the mammalian family of ROCO proteins, characterized by common ROC (Ras of complex proteins) and COR (C-terminal of ROC) domains. In the present paper, we review our recent work showing that DAPK is functionally a ROCO protein; its ROC domain binds and hydrolyses GTP. Furthermore, GTP binding regulates DAPK catalytic activity in a novel manner by enhancing autophosphorylation on inhibitory Ser308, thereby promoting the kinase ‘off’ state. This is a novel mechanism for in cis regulation of kinase activity by the distal ROC domain. The functional similarities between DAPK and the Parkinson's disease-associated protein LRRK2 (leucine-rich repeat protein kinase 2), another member of the ROCO family, are also discussed.

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Origin and diversification of leucine-rich repeat receptor-like protein kinase (LRR-RLK) genes in plants

BMC Evolutionary Biology ◽

10.1186/s12862-017-0891-5 ◽

2017 ◽

Vol 17 (1) ◽

Cited By ~ 58

Author(s):

Ping-Li Liu ◽

Liang Du ◽

Yuan Huang ◽

Shu-Min Gao ◽

Meng Yu

Keyword(s):

Protein Kinase ◽

Leucine Rich Repeat

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

Biochemical Journal ◽

10.1042/bj20100483 ◽

2010 ◽

Vol 430 (3) ◽

pp. 393-404 ◽

Cited By ~ 238

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.

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