Functional Annotation of Intrinsically Disordered Domains by Their Amino Acid Content Using Idd Navigator

Abstract

Function prediction of intrinsically disordered domains (IDDs) using sequence similarity methods is limited by their high mutability and prevalence of low complexity regions. We describe a novel method for identifying similar IDDs by a similarity metric based on amino acid composition and identify significantly overrepresented Gene Ontology (GO) and Pfam domain annotations within highly similar IDDs. Applications and extensions of the proposed method are discussed, in particular with respect to protein functional annotation. We test the predicted annotations in a large-scale survey of IDDs in mouse and find that the proposed method provides significantly greater protein coverage in terms of function prediction than traditional sequence alignment methods like BLAST. As a proof of concept we examined several disorder-containing * The authors wish it to be known that, in their opinion, the first two authors contributed equally to this work. proteins: GRA15 and ROP16, both encoded in the parasitic protozoa T. gondii; Cyclon, a mostly uncharacterized protein involved in the regulation of immune cell death; STIM1, a protein essential for regulating calcium levels in the endoplasmic reticulum. We show that the overrepresented GO terms are consistent with recently-reported biological functions. We implemented the method in the web server IDD Navigator. IDD Navigator is available at

Chemical composition is maintained in poorly conserved intrinsically disordered regions and suggests a means for their classification

“…We have previously shown that amino acid content similarity, instead of sequence similarity, can be used to predict a function associated with an IDR. 13 While the method works better than random, the results here suggest several avenues for improvement, such as location preference. Indeed, location of IDRs has been previously used in the function prediction of proteins with long disordered regions.…”

“…12 Indeed, the use of amino acid content similarity alone can help identify IDRs with similar functions at statistically significant levels. 13 Thus, the amino acid content and the resultant overall chemical composition of the IDR are clearly important. For instance, it has been observed that the amino acid composition, specifically the fraction of Gly residues, is similar in the N-terminal domains of core histones H2A and H4 in spite of poor sequence similarity.…”

FXR1 splicing is important for muscle development and biomolecular condensates in muscle cells

“…Protein disorder was predicted using the IUPRED algorithm (Dosztányi et al, 2005a(Dosztányi et al, , 2005b. The aa composition of the C-terminal IDD of FXR1 was determined using IDD Navigator with IUPRED disordered domain prediction (Patil et al, 2012) along with the ProtParam tool (https://web.expasy.org/protparam/); Wilkins et al, 1999). For phosphorylation prediction, the sequences of the His-GB1-FXR1 A/E, or FMR1 (uniprot) were analyzed using the NETphos 3.1 predictor (serine phosphorylation) and IUPRED (disorder).…”

Biochemistry That Times the Day

“… 42 However, unlike the latter, they possess a disordered C-terminal region, a feature that they share with CLOCK and BMAL1 (where it serves the regulation of their activity) 9 , 43 − 45 as well as PER (where it contains binding sites for kinases and CRY). 46 , 47 The presence of such intrinsically disordered domains (IDDs) 48 is not just a shared property among mammalian clock proteins and other components involved in transcriptional regulation; 49 disordered C-terminal regions also figure prominently in the proteins that assemble the cyanobacterial KaiABC PTO. 17 , 50 A structural and functional understanding of these regions, e.g., the C-terminal tail of KaiB that is important for proper rhythmicity of the cyanobacterial timer, 51 has remained elusive thus far, despite the use of a hybrid structural biology approach to dissect the KaiABC clock.…”

“…Cryptochromes do not share architectural features with CLOCK, BMAL1, and PER proteins because they lack PAS domains but instead contain the PHR that is structurally similar to photolyase . However, unlike the latter, they possess a disordered C-terminal region, a feature that they share with CLOCK and BMAL1 (where it serves the regulation of their activity) ,− as well as PER (where it contains binding sites for kinases and CRY). , The presence of such intrinsically disordered domains (IDDs) is not just a shared property among mammalian clock proteins and other components involved in transcriptional regulation; disordered C-terminal regions also figure prominently in the proteins that assemble the cyanobacterial KaiABC PTO. , A structural and functional understanding of these regions, e.g., the C-terminal tail of KaiB that is important for proper rhythmicity of the cyanobacterial timer, has remained elusive thus far, despite the use of a hybrid structural biology approach to dissect the KaiABC clock . The challenges posed by this “simple clock”, regardless of the application of a battery of structural and molecular biology as well as genetic tools, may offer a lesson for the path ahead in structural studies directed at the cogs and gears of the arguably more complex mammalian clock (DOI: 10.1021/bi500731f).…”