The Mad2 partial unfolding model: Regulating mitosis through Mad2 conformational switching

Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 01/2009; 183(5):761-8. DOI: 10.1083/jcb.200808122
Source: PubMed


The metamorphic Mad2 protein acts as a molecular switch in the checkpoint mechanism that monitors proper chromosome attachment to spindle microtubules during cell division. The remarkably slow spontaneous rate of Mad2 switching between its checkpoint inactive and active forms is catalyzed onto a physiologically relevant time scale by a self-self interaction between its two forms, culminating in a large pool of active Mad2. Recent structural, biochemical, and cell biological advances suggest that the catalyzed conversion of Mad2 requires a major structural rearrangement that transits through a partially unfolded intermediate.

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Available from: James Shorter, Oct 01, 2015
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    • "In fact the presence of a dysbiosis has been reported in CD (Collado et al. 2009) and has also been related to the presence of symptoms in patients on GFD (Sánchez et al. 2011). Conversely, we noticed variations in another verified target of miR-192-5p, MAD2L1 (Georges et al. 2008), implicated in the checkpoint that monitors proper chromosome attachment to spindle microtubules during cell division (Skinner et al. 2008). In presence of an abnormal metaphase alignment, it converts its inactive open form in the active close one and links Bub1-related kinase (BubR1) and cell division cycle 20 (Cdc20) proteins, inhibiting cell Fig. 4 STAT3 mRNA and phosphorylated protein expression. "
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    ABSTRACT: Celiac disease is an intestinal disease which shows different symptoms and clinical manifestations among pediatric and adult patients. These variations could be imputable to age-related changes in gut architecture and intestinal immune system, which could be characterized by gene expression differences possibly regulated by miRNAs. We analyzed a panel of miRNAs and their target genes in duodenal biopsies of Marsh 3AB and 3C pediatric celiac patients, compared to controls. Moreover, to assess variation of expression in plasma samples, we evaluated circulating miRNA levels in controls and patients at diagnosis or on gluten-free diet. We detected a decreased miR-192-5p expression in celiac patients, but no variations in NOD2 and CXCL2, targets previously identified in adults. Conversely, we detected a significant increase in mRNA and protein levels of another target, MAD2L1, protein related to cell cycle control. miR-31-5p and miR-338-3p were down-regulated and their respective targets, FOXP3 and RUNX1, involved in Treg function, resulted up-regulated in celiac patients. Finally, we detected, in celiac patients, an increased expression of miR-21-5p, possibly caused by a regulatory loop with its putative target STAT3, which showed an increased activation in Marsh 3C patients. The analysis of plasma revealed a trend similar to that observed in biopsies, but in presence of gluten-free diet we could not detect circulating miRNAs values comparable to controls. miRNAs and their gene targets showed an altered expression in duodenal mucosa and plasma of celiac disease pediatric patients, and these alterations could be different from adult ones.
    Genes & Nutrition 09/2015; 10(5):482. DOI:10.1007/s12263-015-0482-2 · 2.79 Impact Factor
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    • "Such diffusion and amplification of the inhibitory signal are based on catalytic conformational conversion of Mad2 protein. At unattached kinetochores, the binary complex Mad1- " closed " Mad2 acts as a scaffold for a continuous conversion of the cytosolic " open " Mad2 into " closed " Mad2, which is able to bind Cdc20 and inhibit APC/C activity [32] [33] [34] [35]. "
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    ABSTRACT: Abnormal chromosome number, or aneuploidy, is a common feature of human solid tumors, including oral cancer. Deregulated spindle assembly checkpoint (SAC) is thought as one of the mechanisms that drive aneuploidy. In normal cells, SAC prevents anaphase onset until all chromosomes are correctly aligned at the metaphase plate thereby ensuring genomic stability. Significantly, the activity of this checkpoint is compromised in many cancers. While mutations are rather rare, many tumors show altered expression levels of SAC components. Genomic alterations such as aneuploidy indicate a high risk of oral cancer and cancer-related mortality, and the molecular basis of these alterations is largely unknown. Yet, our knowledge on the status of SAC components in oral cancer remains sparse. In this review, we address the state of our knowledge regarding the SAC defects and the underlying molecular mechanisms in oral cancer, and discuss their therapeutic relevance, focusing our analysis on the core components of SAC and its target Cdc20.
    BioMed Research International 06/2014; 2014:145289. DOI:10.1155/2014/145289 · 3.17 Impact Factor
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    • "It has been proposed that a partially unfolded intermediate state of O-Mad2, consisting of the conserved core structure but with more flexible N-and C-terminal regions, is stabilised by dimerising with the C-Mad2 complex where the latent binding site blocked by the Cterminal of O-Mad2 is then revealed. (Skinner et al. 2008). "
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    ABSTRACT: The classic structure–function paradigm holds that a protein exhibits a single well-defined native state that gives rise to its biological function. Nonetheless, over the past few decades, numerous examples of proteins exhibiting biological function arising from multiple structural states of varying disorder have been identified. Most recently, several examples of ‘metamorphic proteins’, able to interconvert between vastly different native-like topologies under physiological conditions, have been characterised with multiple functions. In this review, we look at the concept of protein metamorphosis in relation to the current understanding of the protein structure–function landscape. Although structural dynamism observed for metamorphic proteins provides a novel source of functional versatility, the dynamic nature of the metamorphic proteins generally makes them difficult to identify and probe using conventional protein structure determination methods. However, as the existence of metamorphic proteins has now been established and techniques enabling the analysis of multiple protein conformers are improving, it is likely that this class will continue to grow in number. KeywordsMetamorphic proteins–Lymphotactin–Mad2–CLIC1
    Biophysical Reviews 09/2011; 3(3):143-153. DOI:10.1007/s12551-011-0053-8
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