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Review
. 2019 May 21:12:121.
doi: 10.3389/fnmol.2019.00121. eCollection 2019.

The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases

Liang Qu  1 , Chao Pan  2 , Shi-Ming He  1   3 , Bing Lang  4   5 , Guo-Dong Gao  1 , Xue-Lian Wang  1 , Yuan Wang  1
Affiliations
Review

The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases

Liang Qu et al. Front Mol Neurosci. .

Abstract

The small GTPases from the Ras superfamily play crucial roles in basic cellular processes during practically the entire process of neurodevelopment, including neurogenesis, differentiation, gene expression, membrane and protein traffic, vesicular trafficking, and synaptic plasticity. Small GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction of neuronal networks, as well as for synaptic function and plasticity. Different subfamilies of small GTPases have been linked to a number of non-neoplastic cerebral diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), intellectual disability, epilepsy, drug addiction, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and a large number of idiopathic cerebral diseases. Here, we attempted to make a clearer illustration of the relationship between Ras superfamily GTPases and non-neoplastic cerebral diseases, as well as their roles in the neural system. In future studies, potential treatments for non-neoplastic cerebral diseases which are based on small GTPase related signaling pathways should be explored further. In this paper, we review all the available literature in support of this possibility.

Keywords: Arf subfamily; Rab subfamily; Ran subfamily; Ras superfamily; Rho subfamily; non-neoplastic cerebral diseases; small GTPases.

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Figures

FIGURE 1
FIGURE 1
The two state of small GTPases. GTP- and GDP-bound state are regulated by GEFs and GAPs. GEFs stimulate the exchange of GDP for GTP, resulting activation of Ras (“ON”). GAPs promote GTP hydrolysis, and return Ras to GDP-bound state (“OFF”).
FIGURE 2
FIGURE 2
Evolutionary relationships of human Ras superfamily. The evolutionary history was inferred using the Neighbor-Joining method. After removing identical sequences, 162 amino acid sequences (Supplementary Table S1) are used for the analysis. All ambiguous positions were removed for each sequence pair. The original classification was indicated by different colors: Ras (lilac), Rho (cyan), Rab (purple), Arf (red), Ran (green), and Unclassified members (blank). Evolutionary analyses were conducted in MEGA7.
FIGURE 3
FIGURE 3
Structures analysis of Ras. The crystal structures of Ras GDP Mg2+ complex (PDB 4q21) is showed (upper). This structure contains five α-helices (A1–A5), six β-strands (B1–B6), and five polypeptide loops (G1–G5) and the position relationship among various parts is displayed (below).
FIGURE 4
FIGURE 4
Conservation analysis of the 167 human G-domain of Ras superfamily and its subfamilies (http://meme-suite.org/). Considering that the Ran only has one sequence and is a branch of Rab subfamily, we incorporate Ran into Rab family.
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