scholarly journals Roco Proteins: GTPases with a Baroque Structure and Mechanism

2019 ◽  
Vol 20 (1) ◽  
pp. 147 ◽  
Author(s):  
Lina Wauters ◽  
Wim Versées ◽  
Arjan Kortholt
Keyword(s):  
Parkinson’S Disease ◽  
Recent Work ◽  
Protein Family ◽  
Leucine Rich Repeat ◽  
Working Mechanism ◽  
Ongoing Debate ◽  
Common Cause ◽  
Physiological Functions ◽  
Working Hypothesis ◽  
Domain Protein

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of genetically inherited Parkinson’s Disease (PD). LRRK2 is a large, multi-domain protein belonging to the Roco protein family, a family of GTPases characterized by a central RocCOR (Ras of complex proteins/C-terminal of Roc) domain tandem. Despite the progress in characterizing the GTPase function of Roco proteins, there is still an ongoing debate concerning the working mechanism of Roco proteins in general, and LRRK2 in particular. This review consists of two parts. First, an overview is given of the wide evolutionary range of Roco proteins, leading to a variety of physiological functions. The second part focusses on the GTPase function of the RocCOR domain tandem central to the action of all Roco proteins, and progress in the understanding of its structure and biochemistry is discussed and reviewed. Finally, based on the recent work of our and other labs, a new working hypothesis for the mechanism of Roco proteins is proposed.

scholarly journals Analysis of the LRRK2 p.G2019S mutation in Colombian Parkinson’s Disease Patients

2015 ◽  
pp. 117-121 ◽  
Author(s):  
Andres Felipe Duque ◽  
Juan Carlos Lopez ◽  
Helena Hernandez ◽  
Bruno Benitez ◽  
Juan Jose Yunis ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson Disease ◽  
Latin American ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Causal Factor ◽  
Leucine Rich Repeat ◽  
Common Cause ◽  
Asymptomatic Control ◽  
Normal Controls

Introduction: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2 or Dardarin) are considered to be a common cause of autosomal dominant and sporadic Parkinson´s disease, but the prevalence of these mutations varies among populations. Objective: to analysed the frequency of the LRRK2 p.G2019S mutation (c.6055G>A transition) in a sample of Colombian patients. Materials and Methods: In the present study we have analysed the frequency of the LRRK2 p.G2019S mutation in 154 patients with familial or sporadic Parkinson Disease, including early and late onset patients, and 162 normal controls. Results: Our results show occurrence of this mutation in two cases (2/154, 1.3%) with classical Parkinson´s signs, and one completely asymptomatic control (1/162, 0.6%). Conclusion: The p.G2019S mutation is not an important causal factor of Parkinson Disease in Colombia having similar frequencies to those reported in other Latin American populations.

Regulation of LRRK2: insights from structural and biochemical analysis

2018 ◽  
Vol 399 (7) ◽  
pp. 637-642 ◽  
Author(s):  
Bernd K. Gilsbach ◽  
Marita Eckert ◽  
Christian Johannes Gloeckner
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Biochemical Analysis ◽  
Leucine Rich Repeat ◽  
Domain Protein ◽  
Mechanistic Understanding ◽  
Intramolecular Activation

Abstract Leucine-rich repeat kinase 2 (LRRK2) is a multi-domain protein and its mutations can lead to Parkinson’s disease. Recent studies on LRRK2 and homologue proteins have advanced our mechanistic understanding of LRRK2 regulation. Here, we summarize the available data on the biochemistry and structure of LRRK2 and postulate three possible layers of regulation, translocation, monomer-dimer equilibrium and intramolecular activation of domains.

scholarly journals Cellular effects of LRRK2 mutations

2012 ◽  
Vol 40 (5) ◽  
pp. 1070-1073 ◽  
Author(s):  
Mark R. Cookson
Keyword(s):  
Parkinson’S Disease ◽  
High Expression ◽  
Leucine Rich Repeat ◽  
Common Cause ◽  
Expression Levels ◽  
Neuronal Viability ◽  
Cellular Effects ◽  
Cellular Models ◽  
Discrete Structures ◽  
Cellular Phenotypes

Mutations in LRRK2 (leucine-rich repeat kinase 2) are a relatively common cause of inherited PD (Parkinson's disease), but the mechanism(s) by which mutations lead to disease are poorly understood. In the present paper, I discuss what is known about LRRK2 in cellular models, focusing specifically on assays that have been used to tease apart the effects of LRRK2 mutations on cellular phenotypes. LRRK2 expression has been suggested to cause loss of neuronal viability, although because it also has a strong effect on the length of neurites on these cells, whether this is true toxicity or not is unclear. Also, LRRK2 mutants can promote the redistribution of LRRK2 from diffuse cytosolic staining to more discrete structures, at least at high expression levels achieved in transfection experiments. The relevance of these phenotypes for PD is not yet clear, and a great deal of work is needed to understand them in more depth.

Identification of indeterminate domain protein family genes associated with flowering time in maize

2019 ◽  
Vol 45 (4) ◽  
pp. 499
Author(s):  
Yun-Fu LI ◽  
Jing-Xian WANG ◽  
Yan-Fang DU ◽  
Hua-Wen ZOU ◽  
Zu-Xin ZHANG
Keyword(s):  
Flowering Time ◽  
Protein Family ◽  
Domain Protein

scholarly journals Manganese toxicity and Saccharomyces cerevisiae Mam3p, a member of the ACDP (ancient conserved domain protein) family

2005 ◽  
Vol 386 (3) ◽  
pp. 479-487 ◽  
Author(s):  
Mei YANG ◽  
Laran T. JENSEN ◽  
Allison J. GARDNER ◽  
Valeria C. CULOTTA
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Integral Membrane Protein ◽  
Manganese Toxicity ◽  
Protein Family ◽  
Neurological Deficits ◽  
Yeast Saccharomyces Cerevisiae ◽  
Conserved Domain ◽  
Genetic Epistasis ◽  
Accumulation Of Metals ◽  
Domain Protein

Manganese is an essential, but potentially toxic, trace metal in biological systems. Overexposure to manganese is known to cause neurological deficits in humans, but the pathways that lead to manganese toxicity are largely unknown. We have employed the bakers' yeast Saccharomyces cerevisiae as a model system to identify genes that contribute to manganese-related damage. In a genetic screen for yeast manganese-resistance mutants, we identified S. cerevisiae MAM3 as a gene which, when deleted, would increase cellular tolerance to toxic levels of manganese and also increased the cell's resistance towards cobalt and zinc. By sequence analysis, Mam3p shares strong similarity with the mammalian ACDP (ancient conserved domain protein) family of polypeptides. Mutations in human ACDP1 have been associated with urofacial (Ochoa) syndrome. However, the functions of eukaryotic ACDPs remain unknown. We show here that S. cerevisiae MAM3 encodes an integral membrane protein of the yeast vacuole whose expression levels directly correlate with the degree of manganese toxicity. Surprisingly, Mam3p contributes to manganese toxicity without any obvious changes in vacuolar accumulation of metals. Furthermore, through genetic epistasis studies, we demonstrate that MAM3 operates independently of the well-established manganese-trafficking pathways in yeast, involving the manganese transporters Pmr1p, Smf2p and Pho84p. This is the first report of a eukaryotic ACDP family protein involved in metal homoeostasis.

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