DISOPRED3: precise disordered region predictions with annotated protein-binding activity

Jones, David T.; Cozzetto, Domenico

doi:10.1093/bioinformatics/btu744

Cited by 812 publications

(796 citation statements)

References 43 publications

Supporting

Mentioning

777

Contrasting

Unclassified

Order By: Relevance

“…1B) were acquired from the Yeast Gene Order Browser (YGOB) (66) and visualized using Jalview (67). Boundaries for the Ste50 IDR (A.A. 151-251) were acquired using disorder predictions from DISOPRED3 (68). IDR boundaries for the Ste50 orthologs were determined via multiple sequence alignment, using the boundaries from the S. cerevisiae Ste50 IDR.…”

Section: Methodsmentioning

confidence: 99%

Selection maintains signaling function of a highly diverged intrinsically disordered region

Zarin

Tsai

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Intrinsically disordered regions (IDRs) are characterized by their lack of stable secondary or tertiary structure and comprise a large part of the eukaryotic proteome. Although these regions play a variety of signaling and regulatory roles, they appear to be rapidly evolving at the primary sequence level. To understand the functional implications of this rapid evolution, we focused on a highly diverged IDR in Saccharomyces cerevisiae that is involved in regulating multiple conserved MAPK pathways. We hypothesized that under stabilizing selection, the functional output of orthologous IDRs could be maintained, such that diverse genotypes could lead to similar function and fitness. Consistent with the stabilizing selection hypothesis, we find that diverged, orthologous IDRs can mostly recapitulate wildtype function and fitness in S. cerevisiae. We also find that the electrostatic charge of the IDR is correlated with signaling output and, using phylogenetic comparative methods, find evidence for selection maintaining this quantitative molecular trait despite underlying genotypic divergence.C urrent predictions suggest that close to 40% of all proteins in eukaryotic organisms are either entirely disordered or contain sizeable regions that are disordered, meaning they do not autonomously fold into defined secondary or tertiary structures (1, 2). These intrinsically disordered regions (IDRs) are thought to have important implications for protein function (3, 4) and are known to play regulatory roles, often through short linear motifs (SLiMs) that control protein-protein interactions, localization, degradation, and posttranslational modifications (5, 6). Although proteome-wide studies have provided in silico evidence for conservation of length (7) and composition (8) in some IDRs, reports of increased rates of insertions and deletions (9-13) and amino acid substitutions (14) in IDRs are indicative of their rapid evolution compared with ordered regions. In addition, although some SLiMs are indeed conserved in IDRs (15-17), others appear in clusters where precise position and number are not conserved (18)(19)(20). Although it is reasonable to assume that conservation of sequence in IDRs is indicative of functional conservation of SLiMs, it is more difficult to interpret the functional consequences of IDRs that are highly diverged at the sequence level: These may represent either nonfunctional sequences evolving in the absence of constraint or weakly constrained functional elements that are gained or lost in a compensatory manner [undergoing evolutionary turnover (as described in refs. 18, 21)], such that they are not conserved at the amino acid sequence level.Like IDRs, noncoding DNA often shows relatively rapid evolution and weak constraints at the sequence level (22). Interestingly, IDRs show other parallels with noncoding DNA (18,23,24). For example, nonconserved clusters of phosphorylation sites in IDRs are reminiscent of nonconserved transcription factor binding sites in enhancers. Although these enhancers and the bi...

show abstract

Section: Methodsmentioning

confidence: 99%

Selection maintains signaling function of a highly diverged intrinsically disordered region

Zarin

Tsai

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Secondary structure prediction was determined using AGADIR helical content predictor (32). Intrinsically disordered tendency was predicted using DISpro (33), PONDR (34), and DISOPRED3 (35).…”

Section: Methodsmentioning

confidence: 99%

The Unstructured N-terminal Region of Arabidopsis Group 4 Late Embryogenesis Abundant (LEA) Proteins Is Required for Folding and for Chaperone-like Activity under Water Deficit

Cuevas-Velazquez

Saab‐Rincón

Reyes

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Late embryogenesis abundant (LEA) proteins are a conserved group of proteins widely distributed in the plant kingdom that participate in the tolerance to water deficit of different plant species. In silico analyses indicate that most LEA proteins are structurally disordered. The structural plasticity of these proteins opens the question of whether water deficit modulates their conformation and whether these possible changes are related to their function. In this work, we characterized the secondary structure of Arabidopsis group 4 LEA proteins. We found that they are disordered in aqueous solution, with high intrinsic potential to fold into ␣-helix. We demonstrate that complete dehydration is not required for these proteins to sample ordered structures because milder water deficit and macromolecular crowding induce high ␣-helix levels in vitro, suggesting that prevalent conditions under water deficit modulate their conformation. We also show that the N-terminal region, conserved across all group 4 LEA proteins, is necessary and sufficient for conformational transitions and that their protective function is confined to this region, suggesting that folding into ␣-helix is required for chaperone-like activity under water limitation. We propose that these proteins can exist as different conformers, favoring functional diversity, a moonlighting property arising from their structural dynamics.

show abstract

“…Indeed, this is how calpastatin recognizes and inhibits calpain-2. Based on SAXS solution structural models with/without Ca 2+ bound and the Ca 2+ -bound crystal structures, we propose that IS1 is intrinsically unstructured as predicted by PSIPRED (27,28) (Fig. 2) and has affinity for an unknown protein.…”

Section: Discussionmentioning

confidence: 99%

“…Selective inhibition of calpain-3 activity may have a sparing effect on those LGMD2A mutants that show accelerated autoproteolytic loss (24). acids (NS), which is predicted by PSIPRED (27,28) to be highly disordered (Fig. 2).…”

mentioning

confidence: 99%

Structures of human calpain-3 protease core with and without bound inhibitor reveal mechanisms of calpain activation

Campbell

Davies

2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Limb-girdle muscular dystrophy type 2a arises from mutations in the Ca 2+ -activated intracellular cysteine protease calpain-3. This calpain isoform is abundant in skeletal muscle and differs from the main isoforms, calpain-1 and -2, in being a homodimer and having two short insertion sequences. The first of these, IS1, interrupts the protease core and must be cleaved for activation and substrate binding. Here, to learn how calpain-3 can be regulated and inhibited, we determined the structures of the calpain-3 protease core with IS1 present or proteolytically excised. To prevent intramolecular IS1 autoproteolysis, we converted the active-site Cys to Ala. Small-angle X-ray scattering (SAXS) analysis of the C129A mutant suggested that IS1 is disordered and mobile enough to occupy several locations. Surprisingly, this was also true for the apo version of this mutant. We therefore concluded that IS1 might have a binding partner in the sarcomere and is unstructured in its absence. After autoproteolytic IS1 removal from the active Cys-129 calpain-3 protease core, we could solve its crystal structures with and without the cysteine protease inhibitors E-64 and leupeptin covalently bound to the active-site cysteine. In each structure, the active state of the protease core was assembled by the cooperative binding of two Ca 2+ ions to the equivalent sites used in calpain-1 and -2.

show abstract

DISOPRED3: precise disordered region predictions with annotated protein-binding activity

Cited by 812 publications

References 43 publications

Selection maintains signaling function of a highly diverged intrinsically disordered region

Selection maintains signaling function of a highly diverged intrinsically disordered region

The Unstructured N-terminal Region of Arabidopsis Group 4 Late Embryogenesis Abundant (LEA) Proteins Is Required for Folding and for Chaperone-like Activity under Water Deficit

Structures of human calpain-3 protease core with and without bound inhibitor reveal mechanisms of calpain activation

Contact Info

Product

Resources

About