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Structure and function of the guanylate kinase-like domain of the MAGUK family scaffold proteins
Jinwei ZHU, Yuan SHANG, Jia CHEN, Mingjie ZHANG
Front Biol. 2012, 7 (5): 379-396.
https://doi.org/10.1007/s11515-012-1244-9
Membrane associated guanylate kinases (MAGUKs) are a family of scaffold proteins that play essential roles in organ development, cell-cell communication, cell polarity establishment and maintenance, and cellular signal transduction. Every member of the MAGUK family contains a guanylate kinase-like (GK) domain, which has evolved from the enzyme catalyzing GMP to GDP conversion to become a protein–protein interaction module with no enzymatic activity. Mutations of MAGUKs are linked to a number of human diseases, including autism and hereditary deafness. In this review, we summarize the structural basis governing cellular function of various members of the MAGUKs. In particular, we focus on recent discoveries of MAGUK GKs as specific phospho-protein interaction modules, and discuss functional implications and connections to human diseases of such regulated MAGUK GK/target interactions.
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Centrosome positioning and primary cilia assembly orchestrate neuronal development
Sneha RAO, Shaoyu GE, Maya SHELLY
Front Biol. 2012, 7 (5): 412-427.
https://doi.org/10.1007/s11515-012-1231-1
Establishment of axon and dendrite polarity, migration to a desired location in the developing brain, and establishment of proper synaptic connections are essential processes during neuronal development. The cellular and molecular mechanisms that govern these processes are under intensive investigation. The function of the centrosome in neuronal development has been examined and discussed in few recent studies that underscore the fundamental role of the centrosome in brain development. Clusters of emerging studies have shown that centrosome positioning tightly regulates neuronal development, leading to the segregation of cell factors, directed neurite differentiation, neuronal migration, and synaptic integration. Furthermore, cilia, that arise from the axoneme, a modified centriole, are emerging as new regulatory modules in neuronal development in conjunction with the centrosome. In this review, we focus on summarizing and discussing recent studies on centrosome positioning during neuronal development and also highlight recent findings on the role of cilia in brain development. We further discuss shared molecular signaling pathways that might regulate both centrosome and cilia associated signaling in neuronal development. Furthermore, molecular determinants such as DISC1 and LKB1 have been recently demonstrated to be crucial regulators of various aspects of neuronal development. Strikingly, these determinants might exert their function, at least in part, via the regulation of centrosome and cilia associated signaling and serve as a link between these two signaling centers. We thus include an overview of these molecular determinants.
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Cellular and molecular mechanisms implicated in pathogenesis of selective neurodegeneration in Huntington’s disease
Jeffrey P. CANTLE, Xiao-Hong LU, Xiaofeng GU, X. William YANG
Front Biol. 2012, 7 (5): 459-476.
https://doi.org/10.1007/s11515-012-1246-7
Huntington’s disease (HD) is one of the most common dominantly-inherited neurodegenerative disorders and is caused by a CAG repeat expansion in the huntingtin gene. HD is characterized by selective degeneration of subpopulations of neurons in the brain, however the precise underlying mechanisms how a ubiquitously expressed disease protein could target specific types of neurons for degeneration remains a critical, yet unanswered question for HD and other major neurodegenerative disorders. In this review, we describe the expanding view of selective neuronal vulnerability in HD, based on recent neuropathological and neuroimaging studies. We will also summarize the systematic effort to define the cell types in which mutant Huntingtin expression is critical for pathogenesis of vulnerable neurons in the striatum and cortex. Finally, we will describe selected, emerging molecular mechanisms that are implicated in selective disease processes in HD. Together, the field has begun to appreciate the distinct molecular pathogenic roles of mutant huntingtin in different cell types that may contribute to the selective neuronal vulnerability, with dissection of such mechanisms likely to yield novel molecular targets for HD therapy.
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Mutation in angiotensin II type 1 receptor disrupts its binding to angiotensin II leading to hypotension: An insight into hydrogen bonding patterns
Arpita KUNDU, Sudha RAMAIAH, Anand ANBARASU
Front Biol. 2012, 7 (5): 477-484.
https://doi.org/10.1007/s11515-012-1241-z
To understand the role of angiotensin II type 1 receptor gene (AGTR1) gene products in relation to hypotension we have analyzed the single nucleotide polymorphisms (SNPs) associated with this gene. This can help us to understand the genetic variations that can alter the function of the gene products. In this present study, we report the polymorphic variant associated with AGTR1 and its weak interaction with angiotensin II (AngII) which leads to hypotension. Out of 1318 SNPs, six are found to be non-synonymous, of which rs1064533 shows significant damaging effect. A missense mutation (T1255G), i.e., from thymine to guanine for rs1064533 in AGTR1 gene results in amino acid substitution from cysteine (Cys) to tryptophan (Trp) in the receptor protein. A strong hydrogen bond exists between Cys289 of native AGTR1 protein and glutamine 167 of AngII. Interestingly, it is replaced by a weak hydrogen bond in the mutant protein between Trp289 (mutant residue) and serine 340. Such a substitution from small, hydrophilic to bulky, hydrophobic residue in AGTR1 protein results in reduced binding affinity of the receptor protein with AngII, leading to hypotension. The results presented from this in silico study will open up new prospect for genetic analysis of AGTR1 gene and will be beneficial to the researchers for understanding the role played by AGTR1 gene in hypotension disease.
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9 articles
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