DisProt in 2024: improving function annotation of intrinsically disordered proteins

Abstract

DisProt (URL: https://disprot.org) is the gold standard database for intrinsically disordered proteins and regions, providing valuable information about their functions. The latest version of DisProt brings significant advancements, including a broader representation of functions and an enhanced curation process. These improvements aim to increase both the quality of annotations and their coverage at the sequence level. Higher coverage has been achieved by adopting additional evidence codes. Quality of annotations has been improved by systematically applying Minimum Information About Disorder Experiments (MIADE) principles and reporting all the details of the experimental setup that could potentially influence the structural state of a protein. The DisProt database now includes new thematic datasets and has expanded the adoption of Gene Ontology terms, resulting in an extensive functional repertoire which is automatically propagated to UniProtKB. Finally, we show that DisProt's curated annotations strongly correlate with disorder predictions inferred from AlphaFold2 pLDDT (predicted Local Distance Difference Test) confidence scores. This comparison highlights the utility of DisProt in explaining apparent uncertainty of certain well-defined predicted structures, which often correspond to folding-upon-binding fragments. Overall, DisProt serves as a comprehensive resource, combining experimental evidence of disorder information to enhance our understanding of intrinsically disordered proteins and their functional implications.

Graphical Abstract

Figure 1.

Comparison of the disorder content at the protein level in DisProt and AlphaFoldDB. The disorder content is calculated as the fraction of disordered residues over the protein sequence length. DisProt disorder content corresponds to the fraction of residues in the consensus, which includes structurally disordered regions. Only DisProt proteins with an AlphaFold structure covering the entire protein sequence in AlphaFoldDB were considered, n = 2356. (A) Correlation of the disorder content between DisProt and AlphaFold when different pLDDT thresholds are selected. (B) Comparison of the disorder content between DisProt and AlphaFold when the AlphaFold pLDDT < 70. The red dotted line represents the linear least-squares regression between the two dimensions, with slope 0.462 ± 0.021 and intercept 0.114 ± 0.009.

Figure 2.

The number of DisProt proteins annotated with functional terms. The statistic is provided for the three Gene Ontology namespaces, as well as for the ‘Disorder function’ aspect from the IDPO ontology. The calculation considers only the first 15 most used annotation terms. Before the calculation, both GO and IDPO terms were propagated to the corresponding ontology root. Proteins with multiple identical annotations, e.g. when different articles report the same experimental evidence, are counted only once.