Structural and functional in silico analysis of LRRK2 missense substitutions

Cardona, Fernando; Tormos-Pérez, Marta; Pérez-Tur, Jordi

doi:10.1007/s11033-014-3111-z

Cited by 22 publications

(25 citation statements)

References 54 publications

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“…The N- terminal part of LRRK2 consists of ARM, ANK, and LRR, while a WD40 domain is present at the C-terminus of LRRK2 (Cardona et al, 2014). All these domains are commonly found in signaling proteins, in which they have often a role in protein–protein interaction.…”

Section: Structure Of the N- And C-terminus Of Lrrk2mentioning

confidence: 99%

“…All these domains are commonly found in signaling proteins, in which they have often a role in protein–protein interaction. Although there are no structures of the N- or C-terminal LRRK2 domains available, these protein–protein domains have a highly conserved fold (Cardona et al, 2014). ARM repeats are about a 42 amino acid long tandem repeat that form a super-helical bundle (Tewari et al, 2010).…”

Section: Structure Of the N- And C-terminus Of Lrrk2mentioning

confidence: 99%

“…One mutation within the ARM domain (Glu334Lys) is associated with PD. In silico modeling predicts that this mutation changes the electrostatic surface of the domain (Cardona et al, 2014). ANK contains seven repetitive motifs which form helix-loop-helix structures that end in a loop or hairpin (Mosavi and Cammett, 2004).…”

Section: Structure Of the N- And C-terminus Of Lrrk2mentioning

confidence: 99%

“…ANK contains seven repetitive motifs which form helix-loop-helix structures that end in a loop or hairpin (Mosavi and Cammett, 2004). Modeling of the PD-related Pro755Leu and Arg793Met mutants predict that these mutations would affect protein stability or the electrostatic surface, respectively (Cardona et al, 2014). LRRs are made of an 11 amino acid long conserved motif LxxLxLxxNxL (Leucines can be replaced by isoleucine, valine or phenylalanine).…”

Section: Structure Of the N- And C-terminus Of Lrrk2mentioning

confidence: 99%

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Structural biology of the LRRK2 GTPase and kinase domains: implications for regulation

Gilsbach

Kortholt

2014

Front. Mol. Neurosci.

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Human leucine rich repeat kinase 2 (LRRK2) belongs to the Roco family of proteins, which are characterized by the presence of a Ras-like G-domain (Roc), a C-terminal of Roc domain (COR), and a kinase domain. Mutations in LRRK2 have been found to be thus far the most frequent cause of late-onset Parkinson’s disease (PD). Several of the pathogenic mutations in LRRK2 result in decreased GTPase activity and enhanced kinase activity, suggesting a possible PD-related gain of abnormal function. Important progress in the structural understanding of LRRK2 has come from our work with related Roco proteins from lower organisms. Atomic structures of Roco proteins from prokaryotes revealed that Roco proteins belong to the GAD class of molecular switches (G proteins activated by nucleotide dependent dimerization). As in LRRK2, PD-analogous mutations in Roco proteins from bacteria decrease the GTPase reaction. Studies with Roco proteins from the model organism Dictyostelium discoideum revealed that PD mutants have different effects and most importantly they explained the G2019S-related increased LRRK2 kinase activity. Furthermore, the structure of Dictyostelium Roco4 kinase in complex with the LRRK2 inhibitor H1152 showed that Roco4 and other Roco family proteins can be important for the optimization of the current, and identification of new, LRRK2 kinase inhibitors. In this review we highlight the recent progress in structural and biochemical characterization of Roco proteins and discuss its implication for the understanding of the complex regulatory mechanism of LRRK2.

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Section: Structure Of the N- And C-terminus Of Lrrk2mentioning

confidence: 99%

Section: Structure Of the N- And C-terminus Of Lrrk2mentioning

confidence: 99%

Section: Structure Of the N- And C-terminus Of Lrrk2mentioning

confidence: 99%

Section: Structure Of the N- And C-terminus Of Lrrk2mentioning

confidence: 99%

See 2 more Smart Citations

Structural biology of the LRRK2 GTPase and kinase domains: implications for regulation

Gilsbach

Kortholt

2014

Front. Mol. Neurosci.

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“…The normal function of LRRK2 is the regulation of kinase and GTPase activities, binding partners, phosphosubstrates. Mutation inLRRK2 leads to enchancedkinase activity and GTP binding that result in cell death 6 . The important pathophysiologys of PD are aggregation of alpha synuclein and the formation of lewy bodies 7 .…”

Section: Introductionmentioning

confidence: 99%

Untitled

2018

IJPSR

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Neurodegenerative disease is the condition of brain cells that lose of its ability to generate the neurotransmitters and this leads to the accumulation of proteins in the brain. These condition causes memory loss and problems in the cognitive functions. Neurological diseases are characterized by four major types such as Alzheimer's disease, Parkinson's disease, Huntington disease, Amyotrophic lateral sclerosis. Parkinson's disease is a second neurological disorder, characterized by a selective loss of dopaminergic neurons in the substantianigra, causing a subsequent reduction of dopamine levels in the striatum. Loss of dopaminergic neurons in striatum causes imbalance of neurotransmitters like acetylcholine and dopamine, resulting in the Parkinson's disease. Tremor, rigidity, dyskinesia are the primary symptoms and memory loss, sleeps disorders, cognitive impairments are the secondary symptoms of Parkinson's. Aim: To investigate the structural changes in silico docking was performedwith target protein LRRK2 with the following compounds theaflavin, baicalein, sesamol, tenuigenin, gastrodin, phloroglucinol and L-DOPA. Methods: The in silico docking was carried out using autodock version 4.2. Rasmol tool was used to visualize the protein structures. Results: The docking energy of L-DOPA with LRRK2 showed binding energy-4.97 Kcal/mol, Kcal/ mol, gastrodin-6.02 Kcal/mol and phloroglucinol as binding energy-4.99 Kcal/mol. Conclusion: These results indicate that the natural plant compounds have more affinity and interact with LRRK2 in a better manner compared to the L-DOPA the standard drug. Therefore natural plant compounds may be helpful in the treatment of Parkinson's disease.

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Association of rare variants in neurodegenerative genes with familial Alzheimer’s disease

Zhang

Jiao

Xiao

et al. 2020

Ann Clin Transl Neurol

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Objective: To investigate the impact of rare variants underlying neurodegenerative-related genes to familial Alzheimer's disease (AD). Methods: We performed targeted sequencing of 277 neurodegenerative-related genes on probands from 75 Chinese AD families non-carrying causative mutation of dementia genes. Rare coding variants segregated in families were tested for association in an independent cohort of 506 patients with sporadic AD and 498 cognitively normal controls. East Asians data from the Exome Aggregation Consortium (ExAC) were used as a reference control. Results: A novel rare variant, P410S of PLD3 was found in an early-onset AD family. LRRK2 I2012T, a causative mutation of Parkinson's disease, was identified in another early-onset AD family. Missense variants in ABCA7 (P143S and A1507T) and CR1 (T239M) were significantly associated with familial AD (P = 0.005437, 0.001383, 0.000549), a missense variant in TREM2(S183C) was significantly associated with AD (P = 0.000396) when compared with the East Asian controls in ExAC database. A non-frameshift variant in FUS (G223del) was frequent in AD cases and significantly associated with familial AD (P = 0.008). Interpretation: Multiple rare coding variants of causal and risk neurodegenerative genes were presented in clinically diagnosed AD families that may confer risk of AD. Our data supported that the clinical, pathological, and genetic architectures of AD, PD, and FTD/ALS may overlapping. We propose that targeted sequencing on neurodegenerative-related genes is necessary for genetically unclear AD families.

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Structural and functional in silico analysis of LRRK2 missense substitutions

Cited by 22 publications

References 54 publications

Structural biology of the LRRK2 GTPase and kinase domains: implications for regulation

Structural biology of the LRRK2 GTPase and kinase domains: implications for regulation

Untitled

Association of rare variants in neurodegenerative genes with familial Alzheimer’s disease

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