Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

Peng, Zhenling; Xue, Bin; Kurgan, Lukasz; Uversky, Vladimir N.

doi:10.1038/cdd.2013.65

Cited by 72 publications

(64 citation statements)

References 58 publications

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“…It has been recently demonstrated that a considerable number of autophagy regulators and effectors bear IDRs, often enriched in regions of protein-protein interaction (Mei et al, 2014;Peng et al, 2013). It has also been shown that the IDRs of Beclin-1 and Atg1 (the yeast ortholog of the human ULK1 complex) fold upon binding to their respective interactors -B-cell lymphoma 2 (Bcl-2) and autophagy-related gene 13 (Atg13) -with these folding events being functional to the dynamic regulation of Beclin-1-Bcl-2 and Atg1-Atg13 complexes (Mei et al, 2014;Stjepanovic et al, 2014).…”

Section: Ambra1 (Un)structurementioning

confidence: 99%

“…Indeed, the intrinsic disorder of Ambra1 accounts for the great plasticity of this protein, making it an excellent scaffold-molecule candidate that is able to coordinate several intracellular processes with autophagy (Mei et al, 2014;Peng et al, 2013). In fact, a number of interaction partners of Ambra1 have been identified and highlight the involvement of Ambra1 in autophagy, apoptosis and the cell cycle (see poster).…”

Section: Introductionmentioning

confidence: 99%

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Ambra1 at a glance

Cianfanelli

Zio

Bartolomeo

et al. 2015

Journal of Cell Science

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The activating molecule in Beclin-1-regulated autophagy (Ambra1), also known as autophagy/Beclin-1 regulator 1, is a highly intrinsically disordered and vertebrate-conserved adapter protein that is part of the autophagy signaling network. It acts in an early step of mammalian target of rapamycin complex 1 (mTORC1)-dependent autophagy by favouring formation of the autophagosome core complex. However, recent studies have revealed that Ambra1 can also coordinate a cell response upon starvation or other stresses that involve translocation of the autophagosome core complex to the endoplasmic reticulum (ER), regulative ubiquitylation and stabilization of the kinase ULK1, selective mitochondria removal and cell cycle downregulation. Moreover, Ambra1 itself appears to be targeted by a number of regulatory processes, such as cullin-dependent degradation, caspase cleavage and several modifications, ranging from phosphorylation to ubiquitylation. Altogether, this complex network of regulation highlights the importance of Ambra1 in crucial physiological events, including metabolism, cell death and cell division. In addition, Ambra1 is an important regulator of embryonic development, and its mutation or inactivation has been shown to correlate with several pathologies of the nervous system and to be involved in carcinogenesis. In this Cell Science at a Glance article and the accompanying poster, we discuss recent advances in the Ambra1 field, particularly the role of this proautophagic protein in cellular pathophysiology.

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Section: Ambra1 (Un)structurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ambra1 at a glance

Cianfanelli

Zio

Bartolomeo

et al. 2015

Journal of Cell Science

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“…Multidomain proteins often possess IDRs that connect folded domains (19). It has recently been shown that more than 30% of eukaryotic proteins possess predicted IDRs and that these are engaged in molecular recognition and signaling and are involved in posttranslational modifications (20,21). For example, phosphorylation sites share biochemical characteristics with IDRs such as amino acid composition, sequence complexity, amino acid charge, or hydrophobicity (22).…”

mentioning

confidence: 99%

Allosteric Interactions by p53 mRNA Govern HDM2 E3 Ubiquitin Ligase Specificity under Different Conditions

Medina-Medina

García-Beltrán

Mora

et al. 2016

Molecular and Cellular Biology

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c HDM2 and HDMX are key negative regulatory factors of the p53 tumor suppressor under normal conditions by promoting its degradation or preventing its trans activity, respectively. It has more recently been shown that both proteins can also act as positive regulators of p53 after DNA damage. This involves phosphorylation by ATM on serine residues HDM2(S395) and HDMX(S403), promoting their respective interaction with the p53 mRNA. However, the underlying molecular mechanisms of how these phosphorylation events switch HDM2 and HDMX from negative to positive regulators of p53 is not known. Our results show that these phosphorylation events reside within intrinsically disordered domains and change the conformation of the proteins. The modifications promote the exposition of N-terminal interfaces that support the formation of a new HDMX-HDM2 heterodimer independent of the C-terminal RING-RING interaction. The E3 ubiquitin ligase activity of this complex toward p53 is prevented by the p53 mRNA ligand but, interestingly, does not affect the capacity to ubiquitinate HDMX and HDM2. These results show how ATM-mediated modifications of HDMX and HDM2 switch HDM2 E3 ubiquitin ligase activity away from p53 but toward HDMX and itself and illustrate how the substrate specificity of HDM2 E3 ligase activity is regulated.T he activity of the RING-E3 ubiquitin ligase HDM2 is tightly regulated by posttranslational modifications and protein-protein interactions that control its subcellular localization and interacting partners (1, 2). The best-characterized activity of HMD2 is the N-terminal interaction between its hydrophobic pocket and the conserved BOX-I domain of p53, which under normal cellular conditions promotes p53 polyubiquitination. The nonredundant HDM2 paralogue HDMX (also called HDM4) is, like HDM2, upregulated in human cancers (3)(4)(5). Despite the similarity with the C-terminal RING domain of HDM2 (approximately 75%), HDMX does not harbor E3 ubiquitin ligase activity toward p53, and its negative activity is instead linked to suppression of p53 trans activity. Mice lacking either mdm2 (the hdm2 mouse orthologous) or mdmx (the hdmx mouse orthologous) die early during development in a p53-dependent manner (6-8). It has been shown more recently that HDMX assists HDM2-mediated degradation of p53 by stabilizing HDM2 via a C-terminal RING-RING interaction and also by promoting HMD2-mediated polyubiquitination of p53 in the cytoplasm (9, 10).The ataxia telangiectasia mutated (ATM) kinase is a key regulator of p53 activity during the double-stranded DNA damage response that helps to induce p53 expression and activity. The direct and indirect phosphorylation of residues within the p53 BOX-I domain of p53 prevents the interaction with HDM2 and is linked to an increase in p53 activity (11-13). The phosphorylation on HDM2 at serine 395 (394 in mouse MDM2) is crucial for p53 stabilization, and animals carrying the S394A mutation have an impaired response to irradiation (14). The corresponding mutation in the human protein prevents ...

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“…Consequently, we had to exclude viruses that were not considered in Ref. [47] and archaea that had small sample size.Similarly as in [48,49], we quantified the sequence conservation using relative entropy [50], which was computed from the Weighted Observed Percentages (WOP) profiles produced by PSI-BLAST [51]. PSI-BLAST was run with default parameters (−j 3, −h 0.001) against the nr database.…”

mentioning

confidence: 99%

Exceptionally abundant exceptions: comprehensive characterization of intrinsic disorder in all domains of life

Peng

Yan

Fan

et al. 2014

Cell. Mol. Life Sci.

342

265

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consensus-based disorder predictions, and for the first time comprehensively characterized intrinsic disorder at proteomic and protein levels from all significant perspectives, including abundance, cellular localization, functional roles, evolution, and impact on structural coverage. We show that intrinsic disorder is more abundant and has a unique profile in eukaryotes. We map disorder into archaea, bacterial and eukaryotic cells, and demonstrate that it is preferentially located in some cellular compartments. Functional analysis that considers over 1,200 annotations shows that certain functions are exclusively implemented by intrinsically disordered proteins and regions, and that some of them are specific to certain domains of life. We reveal that disordered regions are often targets for various post-translational modifications, but primarily in the eukaryotes and viruses. Using a phylogenetic tree for 14 eukaryotic and 112 bacterial species, we analyzed relations between disorder, sequence conservation and evolutionary speed. We provide a complete analysis that clearly shows that intrinsic disorder is exceptionally and uniquely abundant in each domain of life. Keywords Intrinsic disorder · Intrinsically disordered proteins · Intrinsically disordered regions · Cellular localization · Post-translational modifications · Evolutionary speed IntroductionIt is now recognized that in addition to globular, transmembrane and fibrillar proteins that are known to be characterized by unique three dimensional (3D)-structure, there is another tribe of proteins, which, being biologically functional, do not have unique 3D-structures in their native Abstract Recent years witnessed increased interest in intrinsically disordered proteins and regions. These proteins and regions are abundant and possess unique structural features and a broad functional repertoire that complements ordered proteins. However, modern studies on the abundance and functions of intrinsically disordered proteins and regions are relatively limited in size and scope of their analysis. To fill this gap, we performed a broad and detailed computational analysis of over 6 million proteins from 59 archaea, 471 bacterial, 110 eukaryotic and 325 viral proteomes. We used arguably more accurate Electronic supplementary material The online version of this article (doi:10.1007/s00018-014-1661-9) contains supplementary material, which is available to authorized users. 3states under the physiologic conditions in vitro and in vivo [1][2][3][4][5]. The members of this novel tribe are known as intrinsically disordered proteins (IDPs). Their structures are defined as highly dynamic ensembles of flexible conformations, where sampling of a large portion of a polypeptide's available conformational space is allowed. Although IDPs and intrinsically disordered regions (IDRs) in proteins are devoid of stable 3D-structures, they possess crucial biological functions and play multiple important roles in living organisms. In fact, the conformational plasticity associated with intrins...

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Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

Cited by 72 publications

References 58 publications

Ambra1 at a glance

Ambra1 at a glance

Allosteric Interactions by p53 mRNA Govern HDM2 E3 Ubiquitin Ligase Specificity under Different Conditions

Exceptionally abundant exceptions: comprehensive characterization of intrinsic disorder in all domains of life

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