Journal of Molecular Biology

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  • Brainless but Multi-Headed: Decision Making by the Acellular Slime Mould Physarum polycephalum
    [Jul 2015]

    Publication date: Available online 17 July 2015
    Source:Journal of Molecular Biology

    Author(s): Madeleine Beekman, Tanya Latty

    Because of its peculiar biology and the ease with which it can be cultured, the acellular slime mould Physarum polycephalum has long been a model organism in a range of disciplines. Due to its macroscopic, syncytial nature, it is no surprise that it has been a favourite amongst cell biologists. Its inclusion in the experimental tool kit of behavioural ecologists is much more recent. These recent studies have certainly paid off. They have shown that, for an organism that lacks a brain or central nervous system, P. polycephalum shows rather complex behaviour. For example, it is capable of finding the shortest path through a maze, it can construct networks as efficient as those designed by humans, it can solve computationally difficult puzzles, it makes multi-objective foraging decisions, it balances its nutrient intake and it even behaves irrationally. Are the slime mould's achievements simply “cute”, worthy of mentioning in passing but nothing to take too seriously? Or do they hint at the fundamental processes underlying all decision making? We will address this question after reviewing the decision-making abilities of the slime mould.
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    Categories: Journal Articles
  • A Regulated, Ubiquitin-Independent Degron in IκBα
    [Jul 2015]

    Publication date: Available online 17 July 2015
    Source:Journal of Molecular Biology

    Author(s): Karen T. Fortmann, Russell D. Lewis, Kim A. Ngo, Riku Fagerlund, Alexander Hoffmann

    Whereas ubiquitin-dependent degrons have been characterized in some detail, how proteins may be targeted to ubiquitin-independent proteasomal degradation remains unclear. Here we show that IκBα contains an ubiquitin-independent degron whose activity is portable to heterologous proteins such as the globular protein GFP (green fluorescent protein) via a proteasome-dependent, ubiquitin-independent, non-lysosomal pathway. The ubiquitin-independent degradation signal resides in an 11-amino-acid sequence, which is not only sufficient but also required for IκBα's short half-life. Finally, we show that this degron's activity is regulated by the interaction with NFκB, which controls its solvent exposure, and we demonstrate that this regulation of the degron's activity is critical for IκBα's signaling functions.
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  • Structural and functional characterization of a novel family GH115 4-O-Methyl-α-glucuronidase with specificity for decorated arabinogalactans
    [Jul 2015]

    Publication date: Available online 14 July 2015
    Source:Journal of Molecular Biology

    Author(s): Friso Aalbers, Johan P. Turkenburg, Gideon J. Davies, Lubbert Dijkhuizen, Alicia Lammerts van Bueren

    Glycoside hydrolases are clustered into families based on amino acid sequence similarities, and belonging to a particular family can infer biological activity of an enzyme. Family GH115 contains α-glucuronidases where several members have been shown to hydrolyze terminal α-1,2-linked glucuronic acid and 4-O-methylated glucuronic acid from the plant cell wall polysaccharide glucuronoxylan. Other GH115 enzymes show no activity on glucuronoxylan, and therefore it has been proposed that family GH115 may be a poly-specific family. In this study we reveal that a putative periplasmic GH115 from the human gut symbiont Bacteroides thetaiotaomicron, BtGH115A, hydrolyzes terminal 4-O-methyl-gluruconic acid residues from decorated arabinogalactan isolated from acacia tree. The 3-dimensional structure of BtGH115A reveals that BtGH115A has the same domain architecture as the other structurally characterized member of this family, BoAgu115A, however the C-terminal module is located in different positions in each enzyme; in BoAgu115A it facilitates dimerization via interactions with the catalytic domain of the adjacent polypeptide chain while in BtGH115A it associates with the catalytic domain in the same polypeptide chain. Phylogenetic analysis of GH115 amino sequences divide the family into distinct clades which may distinguish different substrate specificities. Finally, we show that BtGH115A α-glucuronidase activity is necessary for the sequential digestion of branched galactans from acacia gum by a galactan-β-1,3-galactosidase from family GH43, however, while B. thetaiotaomicron grows on larch wood arabinogalactan, the bacterium is not able to metabolize acacia gum arabinogalactan, suggesting that BtGH115A is involved in degradation of arabinogalactan fragments liberated by other microbial species in the gastrointestinal tract.
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  • Emerging Roles for Maf1 beyond the Regulation of RNA Polymerase III Activity
    [Jul 2015]

    Publication date: Available online 11 July 2015
    Source:Journal of Molecular Biology

    Author(s): Akshat Khanna, Ajay Pradhan, Sean P. Curran

    Maf1 was first identified in yeast, and studies in metazoans have primarily focused on examining its role in the repression of transcription that is dependent on RNA polymerase III. Recent work has revealed a novel and conserved function for Maf1 in the maintenance of intracellular lipid pools in Caenorhabditis elegans, mice, and cancer cell lines. Although additional Maf1 targets are likely, they have not been identified, and these recent findings begin to define specific activities for Maf1 in multicellular organisms beyond the regulation of RNA polymerase III transcription and suggest that Maf1 plays a more diverse role in organismal physiology. We will discuss these newly defined physiological roles of Maf1 that point to its placement as an important new player in lipid metabolism with implications in human metabolic diseases such as obesity and cancer, which display prominent defects in lipid homeostasis.
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  • The Contribution of Missense Mutations in Core and Rim Residues of Protein–Protein Interfaces to Human Disease
    [Jul 2015]

    Publication date: Available online 11 July 2015
    Source:Journal of Molecular Biology

    Author(s): Alessia David, Michael J.E. Sternberg

    Missense mutations at protein–protein interaction sites, called interfaces, are important contributors to human disease. Interfaces are non-uniform surface areas characterized by two main regions, “core” and “rim”, which differ in terms of evolutionary conservation and physicochemical properties. Moreover, within interfaces, only a small subset of residues (“hot spots”) is crucial for the binding free energy of the protein–protein complex. We performed a large-scale structural analysis of human single amino acid variations (SAVs) and demonstrated that disease-causing mutations are preferentially located within the interface core, as opposed to the rim (p <0.01). In contrast, the interface rim is significantly enriched in polymorphisms, similar to the remaining non-interacting surface. Energetic hot spots tend to be enriched in disease-causing mutations compared to non-hot spots (p =0.05), regardless of their occurrence in core or rim residues. For individual amino acids, the frequency of substitution into a polymorphism or disease-causing mutation differed to other amino acids and was related to its structural location, as was the type of physicochemical change introduced by the SAV. In conclusion, this study demonstrated the different distribution and properties of disease-causing SAVs and polymorphisms within different structural regions and in relation to the energetic contribution of amino acid in protein–protein interfaces, thus highlighting the importance of a structural system biology approach for predicting the effect of SAVs.
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  • Erratum to “Discrete Molecular Dynamics Study of Oligomer Formation by N-Terminally Truncated Amyloid β-Protein” [J. Mol. Biol. 425 (2013) 2260–2275]
    [Jul 2015]

    Publication date: Available online 10 July 2015
    Source:Journal of Molecular Biology

    Author(s): Derya Meral, Brigita Urbanc







    Categories: Journal Articles
  • Metavinculin Tunes the Flexibility and the Architecture of Vinculin-Induced Bundles of Actin Filaments
    [Jul 2015]

    Publication date: Available online 10 July 2015
    Source:Journal of Molecular Biology

    Author(s): Zeynep A. Oztug Durer, Rebecca M. McGillivary, Hyeran Kang, W. Austin Elam, Christina L. Vizcarra, Dorit Hanein, Enrique M. De La Cruz, Emil Reisler, Margot E. Quinlan

    Vinculin is an abundant protein found at cell–cell and cell–extracellular matrix junctions. In muscles, a longer splice isoform of vinculin, metavinculin, is also expressed. The metavinculin-specific insert is part of the C-terminal tail domain, the actin-binding site of both isoforms. Mutations in the metavinculin-specific insert are linked to heart disease such as dilated cardiomyopathies. Vinculin tail domain (VT) both binds and bundles actin filaments. Metavinculin tail domain (MVT) binds actin filaments in a similar orientation but does not bundle filaments. Recently, MVT was reported to sever actin filaments. In this work, we asked how MVT influences F-actin alone or in combination with VT. Cosedimentation and limited proteolysis experiments indicated a similar actin binding affinity and mode for both VT and MVT. In real-time total internal reflection fluorescence microscopy experiments, MVT's severing activity was negligible. Instead, we found that MVT binding caused a 2-fold reduction in F-actin's bending persistence length and increased susceptibility to breakage. Using mutagenesis and site-directed labeling with fluorescence probes, we determined that MVT alters actin interprotomer contacts and dynamics, which presumably reflect the observed changes in bending persistence length. Finally, we found that MVT decreases the density and thickness of actin filament bundles generated by VT. Altogether, our data suggest that MVT alters actin filament flexibility and tunes filament organization in the presence of VT. Both of these activities are potentially important for muscle cell function. Perhaps MVT allows the load of muscle contraction to act as a signal to reorganize actin filaments.
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    Categories: Journal Articles
  • Post-Transcriptional Regulation of Renalase Gene by miR-29 and miR-146 MicroRNAs: Implications for Cardiometabolic Disorders
    [Jul 2015]

    Publication date: Available online 9 July 2015
    Source:Journal of Molecular Biology

    Author(s): Ananthamohan Kalyani, Parshuram J. Sonawane, Abrar Ali Khan, Lakshmi Subramanian, Georg B. Ehret, Ajit S. Mullasari, Nitish R. Mahapatra

    Renalase, a recently identified oxidoreductase, is emerging as a novel regulator of cardiovascular and metabolic disease states. The mechanism of regulation of renalase gene, especially at the post-transcriptional level, is completely unknown. We set out to investigate the possible role of microRNAs in regulation of renalase gene in this study. Computational predictions using multiple algorithms coupled with systematic functional analysis revealed specific interactions of miR-29a/b/c and miR-146a/b with mouse and human renalase 3′-UTR (untranslated region) in cultured cells. Next, we estimated miR-29b and miR-146a, as well as renalase expression, in genetically hypertensive blood pressure high and genetically hypotensive blood pressure low mice. Kidney tissues from blood pressure high mice showed diminished (~1.6- to 1.8-fold) renalase mRNA/protein levels and elevated (~2.2-fold) miR-29b levels as compared to blood pressure low mice. A common single nucleotide polymorphism in human renalase 3′-UTR (C/T; rs10749571) creates a binding site for miR-146a; consistently, miR-146a down-regulated human renalase 3′-UTR/luciferase activity in case of the T allele suggesting its potential role in regulation of renalase in humans. Indeed, genome-wide association studies revealed directionally concordant association of rs10749571 with diastolic blood pressure, glucose and triglyceride levels in large human populations (n ≈58,000–96,000 subjects). This study provides evidence for post-transcriptional regulation of renalase gene by miR-29 and miR-146 and has implications for inter-individual variations on cardiometabolic traits.
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  • Congenital Cataract-Causing Mutation G129C in γC-Crystallin Promotes the Accumulation of Two Distinct Unfolding Intermediates That Form Highly Toxic Aggregates
    [Jul 2015]

    Publication date: Available online 9 July 2015
    Source:Journal of Molecular Biology

    Author(s): Yi-Bo Xi, Xiang-Jun Chen, Wei-Jie Zhao, Yong-Bin Yan

    Cataract is a lens opacification disease prevalent worldwide. Cataract-causing mutations in crystallins generally lead to the formation of light-scattering particles in the lens. However, it remains unclear for the detailed structural and pathological mechanisms of most mutations. In this study, we showed that the G129C mutation in γC-crystallin, which is associated with autosomal dominant congenital nuclear cataract, perturbed the unfolding process by promoting the accumulation of two distinct aggregation-prone intermediates under mild denaturing conditions. The abnormally accumulated intermediates escaped from the chaperone-like function of αA-crystallin during refolding. Molecular dynamics simulations indicated that the mutation altered domain pairing geometry and allowed the penetration of extra solvent molecules into the domain binding interface, thereby weakening domain binding energy. Under mild denaturation conditions, the increased domain movements may facilitate the formation of non-native oligomers via domain swapping, which further assembled into amyloid-like fibrils. The intermediate that appeared at 1.6M guanidine hydrochloride was more compact and less aggregatory than the one populated at 0.9M guanidine hydrochloride, which was caused by the increased solvation of acidic residues in the ion-pairing network via the competitive binding of guanidinium ions. More importantly, both the amyloid-like fibrils preformed in vitro and intracellular aggresomes formed by exogenously overexpressed mutant proteins significantly inhibited cell proliferation and induced cell death. The combined data from spectroscopic, structural and cellular studies strongly suggest that both the formation of light-scattering aggregates and the toxic effects of the aggregates may contribute to the onset and development of cataract.
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    Categories: Journal Articles
  • Gradual folding of an off-pathway molten globule detected at the single-molecule level
    [Jul 2015]

    Publication date: Available online 8 July 2015
    Source:Journal of Molecular Biology

    Author(s): Simon Lindhoud, Menahem Pirchi, Adrie H. Westphal, Gilad Haran, Carlo P.M. van Mierlo

    Molten globules (MGs) are compact, partially folded intermediates that are transiently present during folding of many proteins. These intermediates reside on or off the folding pathway to native protein. Conformational evolution during folding of off-pathway MGs is largely unexplored. Here, we characterize the denaturant-dependent structure of apoflavodoxin’s off-pathway MG. Using single-molecule FRET we follow conversion of unfolded species into MG down to denaturant concentrations that favor formation of native protein. Under strongly denaturing conditions, FRET histograms show a single peak, arising from unfolded protein. The smFRET efficiency distribution shifts to higher value upon decreasing denaturant concentration, because the MG folds. Strikingly, upon approaching native conditions the FRET efficiency of the MG rises above that of native protein. Thus, smFRET exposes the misfolded nature of apoflavodoxin’s off-pathway MG. We show that conversion from unfolded to MG protein is a gradual, second-order like process that simultaneously involves separate regions within the polypeptide.
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  • A New Versatile Immobilization Tag Based on the Ultra High Affinity and Reversibility of the Calmodulin–Calmodulin Binding Peptide Interaction
    [Jul 2015]

    Publication date: Available online 6 July 2015
    Source:Journal of Molecular Biology

    Author(s): Somnath Mukherjee, Marcin Ura, Robert J. Hoey, Anthony A. Kossiakoff

    Reversible, high-affinity immobilization tags are critical tools for myriad biological applications. However, inherent issues are associated with a number of the current methods of immobilization. Particularly, a critical element in phage display sorting is functional immobilization of target proteins. To circumvent these problems, we have used a mutant (N5A) of calmodulin binding peptide (CBP) as an immobilization tag in phage display sorting. The immobilization relies on the ultra high affinity of calmodulin to N5A mutant CBP (RWKKNFIAVSAANRFKKIS) in presence of calcium (K D ~2pM), which can be reversed by EDTA allowing controlled “capture and release” of the specific binders. To evaluate the capabilities of this system, we chose eight targets, some of which were difficult to overexpress and purify with other tags and some had failed in sorting experiments. In all cases, specific binders were generated using a Fab phage display library with CBP-fused constructs. K D values of the Fabs were in subnanomolar to low nanomolar (nM) ranges and were successfully used to selectively recognize antigens in cell-based experiments. Some of these targets were problematic even without any tag; thus, the fact that all led to successful selection endpoints means that borderline cases can be worked on with a high probability of a positive outcome. Taken together with examples of successful case specific, high-level applications like generation of conformation-, epitope- and domain-specific Fabs, we feel that the CBP tag embodies all the attributes of covalent immobilization tags but does not suffer from some of their well-documented drawbacks.
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    Categories: Journal Articles
  • Remaining Mysteries of Molecular Biology: The Role of Polyamines in the Cell
    [Jul 2015]

    Publication date: Available online 5 July 2015
    Source:Journal of Molecular Biology

    Author(s): Leonor Miller-Fleming, Viridiana Olin-Sandoval, Kate Campbell, Markus Ralser

    The polyamines (PAs) spermidine, spermine, putrescine and cadaverine are an essential class of metabolites found throughout all kingdoms of life. In this comprehensive review, we discuss their metabolism, their various intracellular functions and their unusual and conserved regulatory features. These include the regulation of translation via upstream open reading frames, the over-reading of stop codons via ribosomal frameshifting, the existence of an antizyme and an antizyme inhibitor, ubiquitin-independent proteasomal degradation, a complex bi-directional membrane transport system and a unique posttranslational modification—hypusination—that is believed to occur on a single protein only (eIF-5A). Many of these features are broadly conserved indicating that PA metabolism is both concentration critical and evolutionary ancient. When PA metabolism is disrupted, a plethora of cellular processes are affected, including transcription, translation, gene expression regulation, autophagy and stress resistance. As a result, the role of PAs has been associated with cell growth, aging, memory performance, neurodegenerative diseases, metabolic disorders and cancer. Despite comprehensive studies addressing PAs, a unifying concept to interpret their molecular role is missing. The precise biochemical function of polyamines is thus one of the remaining mysteries of molecular cell biology.
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    Categories: Journal Articles
  • Charge Detection Mass Spectrometry Identifies Preferred Non-Icosahedral Polymorphs in the Self-Assembly of Woodchuck Hepatitis Virus Capsids
    [Jul 2015]

    Publication date: Available online 4 July 2015
    Source:Journal of Molecular Biology

    Author(s): Elizabeth E. Pierson, David Z. Keifer, Alexander A. Kukreja, Joseph C.-Y. Wang, Adam Zlotnick, Martin F. Jarrold

    Woodchuck hepatitis virus (WHV) is prone to aberrant assembly in vitro and can form a broad distribution of oversized particles. Characterizing aberrant assembly products is challenging because they are both large and heterogeneous. In this work, charge detection mass spectrometry (CDMS) is used to measure the distribution of WHV assembly products. CDMS is a single-particle technique where the masses of individual ions are determined from simultaneous measurement of each ion's charge and m/z (mass-to-charge) ratio. Under relatively aggressive, assembly promoting conditions, roughly half of the WHV assembly products are T =4 capsids composed of exactly 120 dimers while the other half are a broad distribution of larger species that extends to beyond 210 dimers. There are prominent peaks at around 132 dimers and at 150 dimers. In part, the 150 dimer complex can be attributed to elongating a T =4 capsid along its 5-fold axis by adding a ring of hexamers. However, most of the other features cannot be explained by existing models for hexameric defects. Cryo-electron microscopy provides evidence of elongated capsids. However, image analysis reveals that many of them are not closed but have “spiral-like” morphologies. The CDMS data indicate that oversized capsids have a preference for growth by addition of 3 or 4 dimers, probably by completion of hexameric vertices.
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    Categories: Journal Articles
  • When Too Much ATP Is Bad for Protein Synthesis
    [Jul 2015]

    Publication date: Available online 4 July 2015
    Source:Journal of Molecular Biology

    Author(s): Mauricio H. Pontes, Anastasia Sevostyanova, Eduardo A. Groisman

    Adenosine triphosphate (ATP) is the energy currency of living cells. Even though ATP powers virtually all energy-dependent activities, most cellular ATP is utilized in protein synthesis via tRNA aminoacylation and guanosine triphosphate regeneration. Magnesium (Mg2+), the most common divalent cation in living cells, plays crucial roles in protein synthesis by maintaining the structure of ribosomes, participating in the biochemistry of translation initiation and functioning as a counterion for ATP. A non-physiological increase in ATP levels hinders growth in cells experiencing Mg2+ limitation because ATP is the most abundant nucleotide triphosphate in the cell, and Mg2+ is also required for the stabilization of the cytoplasmic membrane and as a cofactor for essential enzymes. We propose that organisms cope with Mg2+ limitation by decreasing ATP levels and ribosome production, thereby reallocating Mg2+ to indispensable cellular processes.
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    Categories: Journal Articles
  • Editorial Board
    [Jul 2015]

    Publication date: 3 July 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 13









    Categories: Journal Articles
  • Contents List
    [Jul 2015]

    Publication date: 3 July 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 13









    Categories: Journal Articles
  • The Tail-End Is Only the Beginning: NMR Study Reveals a Membrane-Bound State of BCL-XL
    [Jul 2015]

    Publication date: 3 July 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 13

    Author(s): R. Blake Hill, Kevin R. MacKenzie, Megan Cleland Harwig







    Categories: Journal Articles
  • Conformation of BCL-XL upon Membrane Integration
    [Jul 2015]

    Publication date: 3 July 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 13

    Author(s): Yong Yao, Lynn M. Fujimoto, Nathan Hirshman, Andrey A. Bobkov, Antonella Antignani, Richard J. Youle, Francesca M. Marassi

    BCL-XL is an anti-apoptotic BCL-2 family protein found both in the cytosol and bound to intracellular membranes. Structural studies of BCL-XL have advanced by deleting its hydrophobic C-terminus and adding detergents to enhance solubility. However, since the C-terminus is essential for function and detergents strongly affect structure and activity, the molecular mechanisms controlling intracellular localization and cytoprotective activity are incompletely understood. Here we describe the conformations and ligand binding activities of water-soluble and membrane-bound BCL-XL, with its complete C-terminus, in detergent-free environments. We show that the C-terminus interacts with a conserved surface groove in the water-soluble state of the protein and inserts across the phospholipid bilayer in the membrane-bound state. Contrary to current models, membrane binding does not induce a conformational change in the soluble domain and both states bind a known ligand with affinities that are modulated by the specific state of the protein.
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    Categories: Journal Articles
  • Genetic Basis of Common Human Disease: Insight into the Role of Missense SNPs from Genome-Wide Association Studies
    [Jul 2015]

    Publication date: 3 July 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 13

    Author(s): Lipika R. Pal, John Moult

    Recent genome-wide association studies (GWAS) have led to the reliable identification of single nucleotide polymorphisms (SNPs) at a number of loci associated with increased risk of specific common human diseases. Each such locus implicates multiple possible candidate SNPs for involvement in disease mechanism. A variety of mechanisms may link the presence of an SNP to altered in vivo gene product function and hence contribute to disease risk. Here, we report an analysis of the role of one of these mechanisms, missense SNPs (msSNPs) in proteins in seven complex trait diseases. Linkage disequilibrium information was used to identify possible candidate msSNPs associated with increased disease risk at each of 356 loci for the seven diseases. Two computational methods were used to estimate which of these SNPs has a significant impact on in vivo protein function. 69% of the loci have at least one candidate msSNP and 33% have at least one predicted high-impact msSNP. In some cases, these SNPs are in well-established disease-related proteins, such as MST1 (macrophage stimulating 1) for Crohn's disease. In others, they are in proteins identified by GWAS as likely candidates for disease relevance, but previously without known mechanism, such as ADAMTS13 (ADAM metallopeptidase with thrombospondin type 1 motif, 13) for coronary artery disease. In still other cases, the missense SNPs are in proteins not previously suggested as disease candidates, such as TUBB1 (tubulin, beta 1, class VI) for hypertension. Together, these data support a substantial role for this class of SNPs in susceptibility to common human disease.
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    Categories: Journal Articles
  • RING E3-Catalyzed E2 Self-Ubiquitination Attenuates the Activity of Ube2E Ubiquitin-Conjugating Enzymes
    [Jul 2015]

    Publication date: 3 July 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 13

    Author(s): Prerana Agarwal Banka, Adaitya Prasad Behera, Sayani Sarkar, Ajit B. Datta

    Ubiquitination of a target protein is accomplished through sequential actions of the E1, E2s, and the E3s. E2s dictate the modification topology while E3 ligases confer substrate specificity and recruit the cognate E2. Human genome codes for ~35 different E2 proteins; all of which contain the characteristic ubiquitin-conjugating UBC core domain sufficient for catalysis. Many of these E2 enzymes also have N- or C-terminal extensions; roles of which are not very well understood. We show that the N-terminal extension of Ube2E1 undergoes intramolecular auto-ubiquitination. This self-ubiquitination activity is enhanced in the presence of interacting RING E3 ligases and results in a progressive attenuation of the E2 activity toward substrate/E3 modification. We also find that the N-terminal ubiquitination sites are conserved in all the three Ube2Es and replacing them with arginine renders all three full-length Ube2Es equally active as their core UBC domains. Based on these results, we propose that E3-catalyzed self-ubiquitination acts as a key regulatory mechanism that controls the activity of Ube2E class of ubiquitin E2s.
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    Categories: Journal Articles