The Jpred 3 secondary structure prediction server

Callebaut, Christian; Barber, Jonathan D.; Barton, Geoffrey J.

doi:10.1093/nar/gkn238

Cited by 1,349 publications

(1,151 citation statements)

References 32 publications

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“…A region of some limited protection (residues 45-75) encompasses two smaller regions of highly conserved residues (49 -53 and 61-73), and also lies within an area with the predicted secondary structure. Interestingly, these moderately protected areas of predicted secondary structure also appear in the secondary structure prediction for pro-IL-1␣ (64). Fig.…”

Section: The N Terminus Region Of Pro-il-1␤ (Residues 1-116) Displaysmentioning

confidence: 59%

Pro-interleukin (IL)-1β Shares a Core Region of Stability as Compared with Mature IL-1β While Maintaining a Distinctly Different Configurational Landscape

Hailey¹,

Andersen³

et al. 2009

Journal of Biological Chemistry

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Interleukin-1␤ (IL-1␤) is a master cytokine involved in initiating the innate immune response in vertebrates (Dinarello, C. A. (1994) FASEB J. 8, 1314 -1325). It is first synthesized as an inactive 269-residue precursor (pro-interleukin-1␤ or pro-IL-1␤). Pro-IL-1␤ requires processing by caspase-1 to generate the active, mature 153-residue cytokine. In this study, we combined hydrogen/deuterium exchange mass spectrometry, circular dichroism spectroscopy, and enzymatic digestion comparative studies to investigate the configurational landscape of pro-IL-1␤ and the role the N terminus plays in modulating the landscape. We find that the N terminus keeps pro-IL-1␤ in a protease-labile state while maintaining a core region of stability in the C-terminal region, the eventual mature protein. In mature IL-1␤, this highly protected region maps back to the area protected earliest in the NMR studies characterizing an on-route kinetic refolding intermediate. This protected region also encompasses two important functional loops that participate in the IL-1␤/receptor binding interface required for biological activity. We propose that the purpose of the N-terminal precursor region in pro-IL-1␤ is to suppress the function of the eventual mature region while keeping a structurally and also functionally important core region primed for the final folding into the native, active state of the mature protein. The presence of the self-inhibiting precursor region provides yet another layer of regulation in the life cycle of this important cytokine.Nearly all cell types respond to interleukin (IL)-1␤, 4 in a very sensitive manner, via binding to the interleukin-1 receptor type 1 (IL-1RI) (2). Although essential in the immune response, overproduction of IL-1␤ can lead to both acute (sepsis) as well as chronic (rheumatoid arthritis, atherosclerosis, obesity, and diabetes) disease states (3). Thus, the expression, activation, and secretion of this cytokine are tightly controlled (4). Although many cell types express IL-1␤, it is predominately produced and secreted by monocytes and macrophages (1). The protein is synthesized as a biologically inactive 269-residue precursor molecule, pro-interleukin-1␤ (pro-IL-1␤), and the 153-residue active mature IL-1␤ is generated from the C-terminal domain. Processing of the proprotein involves the recently discovered NALP-1 and NALP-3 inflammasomes, which are responsible for activating procaspase-1 (5). The inflammasome function is integral in wound repair as well as for combating infection (6 -9).In vivo, the 31-kDa pro-IL-1␤ precursor is processed to the active C-terminal 17-kDa form by the interleukin-1 converting enzyme, caspase-1 (10, 11). Caspase-1 is a cysteine protease that recognizes two cleavage sites in pro-IL-1␤, the Asp 27 2Gly 28 and Asp 116 2Ala 117 peptide bonds (Fig. 1A). These cleavage sites are conserved across mammals (12-14). The activation pathway is believed to proceed with cleavage first at Asp 27 2Gly 28 (site 1) followed by Asp 116 2Ala 117 (site 2). These processing events lead ...

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Section: The N Terminus Region Of Pro-il-1␤ (Residues 1-116) Displaysmentioning

confidence: 59%

Pro-interleukin (IL)-1β Shares a Core Region of Stability as Compared with Mature IL-1β While Maintaining a Distinctly Different Configurational Landscape

Hailey¹,

Andersen³

et al. 2009

Journal of Biological Chemistry

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“…For proteins and domains without known structure, we considered putative structural templates detected by HHpred, 45 iTASSER 46,47 and known structures for proteins of similar function from other families of RNA virus in PDB and ECOD databases. 48 Once a candidate structural template was detected, we further validated its relationship to the Ebolavirus protein by similarity in function, compatibility between the predicted secondary structure 49 of the Ebolavirus protein and the 3D structure of the template, conservation of residues in the Ebolavirus protein that were aligned to the active sites of the template, and the consistency among multiple structural templates. Sequences of the structural templates and the ZEBOV protein were aligned by Promals3D 50,51 and the alignments were manually adjusted to ensure that the corresponding secondary structure elements in different templates were aligned together.…”

Section: Sequence Analysis Of Ebolavirus Proteinsmentioning

confidence: 99%

Predictive and comparative analysis of Ebolavirus proteins

2015

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Ebolavirus is the pathogen for Ebola Hemorrhagic Fever (EHF). This disease exhibits a high fatality rate and has recently reached a historically epidemic proportion in West Africa. Out of the 5 known Ebolavirus species, only Reston ebolavirus has lost human pathogenicity, while retaining the ability to cause EHF in long-tailed macaque. Significant efforts have been spent to determine the three-dimensional (3D) structures of Ebolavirus proteins, to study their interaction with host proteins, and to identify the functional motifs in these viral proteins. Here, in light of these experimental results, we apply computational analysis to predict the 3D structures and functional sites for Ebolavirus protein domains with unknown structure, including a zinc-finger domain of VP30, the RNA-dependent RNA polymerase catalytic domain and a methyltransferase domain of protein L. In addition, we compare sequences of proteins that interact with Ebolavirus proteins from RESTV-resistant primates with those from RESTV-susceptible monkeys. The host proteins that interact with GP and VP35 show an elevated level of sequence divergence between the RESTV-resistant and RESTV-susceptible species, suggesting that they may be responsible for host specificity. Meanwhile, we detect variable positions in protein sequences that are likely associated with the loss of human pathogenicity in RESTV, map them onto the 3D structures and compare their positions to known functional sites. VP35 and VP30 are significantly enriched in these potential pathogenicity determinants and the clustering of such positions on the surfaces of VP35 and GP suggests possible uncharacterized interaction sites with host proteins that contribute to the virulence of Ebolavirus.

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“…Similar sequences were determined using BLAST (54) as implemented by the ExPASy Proteomics Server (55). Secondary structure prediction was performed using the Jpred3 server (56).…”

Section: Synthesis Of Snac and Coa Tyrosine And Phenylalaninementioning

confidence: 99%

Structural Characterization of OxyD, a Cytochrome P450 Involved in β-Hydroxytyrosine Formation in Vancomycin Biosynthesis

Cryle

Meinhart

Schlichting

2010

Journal of Biological Chemistry

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The cytochrome P450 OxyD from the balhimycin glycopeptide antibiotic biosynthetic operon of Amycolatopsis mediterranei is involved in the biosynthesis of the modified amino acid ␤-R-hydroxytyrosine, an essential precursor for biosynthesis of the vancomycin-type aglycone. OxyD binds the substrate tyrosine not free in solution, but rather covalently linked to the carrier protein (CP) domain of the non-ribosomal peptide synthase BpsD, exhibiting micromolar binding affinity to a tyrosineloaded carrier protein construct. The crystal structure of OxyD was determined to 2.1-Å resolution, revealing a potential binding site for the carrier protein-bound substrate in a different orientation to that seen with the acyl carrier protein-bound P450 BioI Hydroxylated amino acid residues are widely utilized in nature as precursors for complex natural products (see Fig. 1). The oxidative modification of amino acids at the ␤-position is a process that occurs in many different classes of medicinally important biomolecules, including the vancomycin-type antibiotics (reviewed in Refs. 2, 3). These glycopeptide antibiotics have had great clinical success in treating Gram-positive bacterial infections that are resistant to other classes of antibiotics and function through blocking cell wall biosynthesis via complex formation with the cell wall precursor peptidoglycan peptidyl units terminating in -Lys-D-Ala-D-Ala (2, 3). The biosynthesis of the vancomycin peptide requires the incorporation of two amino acid residues derived from ␤-R-hydroxytyrosine. Another group of medicinally important molecules that contain hydroxylated amino acid residues is the aminocoumarincontaining angucycline family of antibiotic compounds, which include coumermycin A, clorobiocin, and simocyclinone and act upon bacterial DNA gyrase. ␤-R-Hydroxytyrosine is an essential precursor in the biosynthesis of these types of antibiotics, where it is needed for the formation of both the A (Fig. 1, blue) and B (Fig. 1, red) rings in the aminocoumarin core. Further examples of the incorporation of hydroxylated amino acids into the biosyntheses of medicinally important compounds can be found in the biosyntheses of the nikkomycin-type antibiotics, zorbamycin and echinomycin ( Fig. 1) (4 -7).Despite the large structural difference in the compounds highlighted above and the difference in the biosyntheses of the compounds overall, the formation of the ␤-hydroxyamino acid precursors follows a conserved route. This involves the oxidation of the amino acid by a member of the cytochrome P450 (P450) 2 superfamily. P450s form a superfamily of heme containing monoxygenases that catalyze a vast array of biologically important transformations (8). The archetypical P450 reaction is the hydroxylation of unactivated C-H bonds, a difficult oxidation made more impressive by the ability of P450s to utilize their oxidative power both regio-and stereoselectively. Many P450s play important roles in natural product biosyntheses, where such selectivity is channeled toward the synthesis of comp...

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The Jpred 3 secondary structure prediction server

Cited by 1,349 publications

References 32 publications

Pro-interleukin (IL)-1β Shares a Core Region of Stability as Compared with Mature IL-1β While Maintaining a Distinctly Different Configurational Landscape

Pro-interleukin (IL)-1β Shares a Core Region of Stability as Compared with Mature IL-1β While Maintaining a Distinctly Different Configurational Landscape

Predictive and comparative analysis of Ebolavirus proteins

Structural Characterization of OxyD, a Cytochrome P450 Involved in β-Hydroxytyrosine Formation in Vancomycin Biosynthesis

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