Table 1. Classifications of Intrinsically Disordered Regions and Proteins.

basis for classification		classes	description	examples
function	(33,39,57,58)	•entropic chains	IDRs carrying out functions that benefit directly from their conformational disorder, e.g., flexible linkers and spacers	MAP2 projection domain, titin PEVK domain, RPA70, MDA5
		•display sites	flexibility of IDRs facilitates exposure of motifs and easy access for proteins that introduce and read PTMs	p53, histone tails, p27, CREB kinase-inducible domain
		•chaperones	their binding properties (many different partners, rapid association/disassociation, and folding upon binding) make IDPs suitable for chaperone functions	hnRNP A1, GroEL, α-crystallin, Hsp33
		•effectors	folding upon binding mechanics allow effectors to modify the activity of their partner proteins	p21, p27, calpastatin, WASP GTPase-binding domain
		•assemblers	assembling IDRs have large binding interfaces that scaffold multiple binding partners and promote the formation of higher-order protein complexes	ribosomal proteins L5, L7, L12, L20, Tcf 3/4, CREB transactivator domain, Axin
		•scavengers	disordered scavengers store and neutralize small ligands	chromogranin A, Pro-rich glycoproteins, caseins and other SCPPs
functional features	linear motifs47,125	•structural modification	sites of conformational alteration of a peptide backbone	peptidylprolyl cis–trans isomerase Pin1 sites
		•proteolytic cleavage	sites of post-translational processing events or proteolytic cleavage scission sites	Caspase-3/-7, separase, taspase1 scission sites
		•PTM removal/addition	specific binding sequences that recruit enzymes catalyzing PTM moiety addition or removal	cyclin-dependent kinase phosphorylation site, SUMOylation site, N-glycosylation site
		•complex promoting	motifs that mediate protein–protein interactions important for complex formation; often associated with signal transduction	proline-rich SH3-binding motif, cyclin box, pY SH2-binding motif, PDZ-binding motif, TRAF-binding motifs in MAVS
		•docking	motifs that increase the specificity and efficiency of modification events by providing an additional binding surface	KEN box degron, MAPK docking sites
		•targeting or trafficking	signal sites that localize proteins within particular subcellular organelles or act to traffic proteins	nuclear localization signal, clathrin box motif, endocytosis adaptor trafficking motifs
	molecular recognition features (MoRFs)121	•alpha	disordered motifs that form α-helices upon target binding	p53 ∼ Mdm2, p53 ∼ RPA70, p53 ∼ S100B(ββ), RNase E ∼ enolase, inhibitor IA3 ∼ proteinase A
		•beta	disordered motifs that form β-strands upon target binding	RNase E ∼ polynucleotide phosphorylase, Grim ∼ DIAP1, pVIc ∼ adenovirus 2 proteinase
		•iota	disordered motifs that form irregular secondary structure upon target binding	p53 ∼ Cdk2-cyclin A, amphiphysin ∼ α-adaptin C
		•complex	disordered motifs that contain combinations of different types of secondary structure upon target binding	amyloid β A4 ∼ X11, WASP ∼ Cdc42
	intrinsically disordered domains (IDDs)158,159		some protein domains identified using sequence-based approaches are fully or largely disordered	WH2, RPEL, BH3, KID domains
	co-occurrence of protein domains with disordered regions161,162		particular disordered regions frequently co-occur in the same sequence with specific protein domains
structure	structural continuum37		proteins function within a continuum of differently disordered conformations, extending from fully structured to completely disordered, with everything in between and no strict boundaries between the states
	protein quartet32,34,166	•intrinsic coil	flexible regions of extended conformation with hardly any secondary structure; high net charge differentiates these from disordered globules	ribosomal proteins L22, L27, 30S, S19, prothymosin α
		•pre-molten globule	disordered protein regions with residual secondary structure, often poised for folding upon binding events; lower net charge makes them more compact than coils	Max, ribosomal proteins S12, S18, L23, L32, calsequestrin
		•molten globule	globally collapsed conformation with regions of fluctuating secondary structure	nuclear coactivator binding domain of CREB binding protein
		•folded	structured proteins with a defined three-dimensional structure	most enzymes, transmembrane domains, hemoglobin, actin
sequence	sequence–structural ensemble relationships166,204	•polar tracts	sequence stretches enriched in polar amino acids often form globules that are generally devoid of significant secondary structure preferences	Asn- and Gly-rich sequences, Gln-rich linkers in transcription factors and RNA-binding proteins
		•polyelectrolytes	amino acid compositions biased toward charged residues of one type; strong polyelectrolytes (high net charge) form expanded coils	Arg-rich protamines, Glu/Asp-rich prothymosin α
		•polyampholytes	sequences with roughly equal numbers of positive and negative charges; conformations of polyampholytes are governed by the linear distribution of oppositely charged residues, with segregation of opposite charges leading to globules, while well-mixed charged sequences adopt random-coil or globular conformations, depending on the total charge	RNA chaperones, splicing factors, titin PEVK domain, yeast prion Sup35
	prediction flavors205	•V	predicted best by the VL-2V predictor, for which the hydrophobic amino acids are the most influential attributes	E. coli ribosomal proteins
		•C	VL-2C is the best predictor for flavor C, which has more histidine, methionine, and alanine residues than the other flavors	poly- and oligosaccharide binding domains
		•S	flavor with less histidine than the others, best predicted by predictor VL-2S, which has a measure of sequence complexity as the most important attribute	proteins that facilitate binding and interaction
	disorder–sequence complexity206		IDPs from different functional classes show distinct disorder–sequence complexity distributions	proteins with disordered linkers between structured domains populate compact and disordered DC regions
	overall degree of disorder35,51,68,161,208,209	•fraction	categorization of proteins based on the fraction of residues predicted to be disordered	0–10/10–30/30–100% disorder
		•overall score	overall disorder scores for the whole protein	minimum average disorder score depending on the predictor
		•continuous stretches	presence or absence of continuous stretches of disordered residues	typically >30 residues
	length of disordered regions211	•>500 residues	proteins that contain disordered regions of different lengths are enriched for different types of functions	transcription
		•300–500 residues		kinase and phosphatase functions
		•<50 residues		(metal) ion binding, ion channels, GTPase regulatory activity
	position of disordered regions211	•N-terminal	proteins that contain disordered regions at different locations in the sequence are enriched for different types of functions	DNA-binding, ion channel
		•internal		transcription regulator, DNA-binding
		•C-terminal		transcription repressor/activator, ion channel
	tandem repeats217,218	•Q/N	glutamine- and asparagine-rich proteins regions are both important for normal cellular function and prone to cause harmful aggregation	huntingtin, Sup35p, Ure2p, Ccr4, Pop2
		•S/R	tandem repeats composed of arginine and serine residues are phosphorylated and disordered, and play a role in spliceosome assembly	ASF/SF2, SRp75, SRSF1
		•K/A/P	tandem repeats composed of lysine, alanine, and proline function in binding nucleosome linker DNA	histone H1
		•F/G	disordered domains with phenylalanine-glycine repeats influence NPC gating behavior	nucleoporins
		•P/T/S	extensively glycosylated regions rich in proline, threonine, and serine residues are involved in mucus formation	mucins
		•others
protein interactions	fuzzy complexes by topology242	•polymorphic	a form of static disorder, with alternative bound conformations serving distinct functions by having different effects on the binding partner	β-catenin ∼ Tcf4, NLS ∼ importin-α, actin ∼ WH2 domain
		•clamp	complex formation through folding upon binding of two disordered protein segments, connected by a linker that remains disordered	Ste5 ∼ Fus3, myosin VI ∼ actin filament, Oct-1 ∼ DNA
		•flanking	complex formation through folding upon binding of a central disordered protein segment, flanked by two regions that remain disordered	SF1 splicing factor ∼ U2AF, proline-rich peptides ∼ SH3 domains, p27Kip1 ∼ cyclin-Cdk2
		•random	disordered regions that remain highly dynamic even in the bound state	elastin self-assembly, Sic1 ∼ Cdc4
	fuzzy complexes by mechanism176,251	•conformational selection	the fuzzy region facilitates the formation of the binding-competent form by shifting the conformational equilibrium	Max ∼ DNA, MeCP2 ∼ DNA
		•flexibility modulation	the fuzzy region modulates the flexibility of the binding interface and changes binding entropy	Ets-1 ∼ DNA, SSB ∼ DNA
		•competitive binding	the fuzzy region serves as an intramolecular competitive partner for the binding surface.	HMGB1 ∼ DNA, RNase1 ∼ RNase inhibitor
		•tethering	the fuzzy region increases the local concentration of a weak-affinity binding domain near the target, or anchors it via transient interactions	RPA ∼ DNA, UPF1 ∼ UPF2, PC4 ∼ VP16
	binding plasticity257	•static	mono-/polyvalent complexes, chameleons, penetrators, huggers	for examples, see Figure 12
		•coiled-coil based	intertwined strings, long cylindrical containers, connectors, armature, tweezers and forceps, grabbers, tentacles, pullers, stackers
		•dynamic	cloud contacts and protein interaction ensembles
evolution	sequence conservation54	•flexible	regions that require the property of disorder for functionality regardless of the exact sequence	signaling and regulatory proteins (Sky1, Bur1)
		•constrained	regions of conserved disorder that also have highly conserved amino acid sequences	ribosomal proteins (Rpl5), protein chaperones (Hsp90)
		•nonconserved	no conservation of the disorder, nor of the underlying sequence; no clear functional hallmarks	yeast Ty1 retrotransposon domains A and B
	conservation of amino acid composition260	•HR	IDRs with high residue conservation	transcription regulation and DNA binding
		•LRHT	IDRs with low residue conservation but high conservation of the amino acid composition of the region	ATPase and nuclease activities
		•LRLT	IDRs with neither conservation of sequence nor conservation of amino acid composition	(metal) ion binding proteins
	lineage and species specificity159	•prokaryotes	species from different kingdoms of life seem to use disorder for different types of functions	longer lasting interactions involved in complex formation
		•eukaryotes and viruses		transient interactions in signaling and regulation
	evolutionary history and mechanism of repeat expansion61	•Type I	repeats that showed no function diversification after expansion	titin PEVK domain, salivary proline-rich proteins
		•Type II	repeats that acquired diverse functions through mutation or differential location within the sequence	RNA polymerase II (CTD)
		•Type III	repeats that gained new functions as a consequence of their expansion	prion protein octarepeats
regulation	expression patterns208	•constitutive	IDPs encoded by constitutively highly expressed transcripts are almost entirely disordered and often ribosomal proteins	ribosomal L proteins
		•high	IDP-encoding transcripts showing high expression levels in most tissues and little tissue specificity	protease inhibitors, splicing factors, complex assemblers
		•medium	these IDP-encoding transcripts are expressed at medium levels, with some tissue-specificity	DNA binding, transcription regulation
		•tissue-specific	IDP-encoding transcripts with highly tissue-specific expression	cell organization regulators, complex disassemblers
		•low or transient	IDP-encoding transcripts that are present in undetectable amounts; more than one-half of analyzed IDPs	variety of functions
	alternative splicing304,305,309,312,313		regulation and evolutionary patterns of inclusion and exclusion of IDR-encoding exons can provide insights into whether the encoded IDR functions in protein regulation and interactions	a tissue-specific region with a phosphosite in the TJP1 protein in mouse, a mammalian-specific region in the PTB1 splicing regulator
	degradation kinetics315,316,318,320,321	•degradation accelerators	IDRs that can influence and accelerate proteasomal degradation of the protein containing it
		•others	IDRs that have no influence on protein half-life or increase it, e.g., because of sequence compositions that impede proteasome processivity	low complexity sequences such as glycine-alanine repeats and polyglutamine repeats
	post-translational processing and secretion337,340		secreted proteins are depleted for IDPs, but structural disorder is important in, e.g., prohormones, the extracellular matrix, and biomineralization	pre-pro-opiomelanocortin, elastic fiber proteins, SIBLINGs, mucins
biophysical properties	solubility209		the sequence features of IDPs are generally associated with aqueous solubility, although some IDPs are thermostable, while others are not; this is likely modulated by sequence–structural ensemble relationships, such as the degree of compaction	4E-BP1, calpastatin, CREB, p21, p27, Sp1, stathmin, WASP
	phase transition137,353		certain IDRs (such as those that contain specific low-complexity regions or interaction motifs) can undergo phase transitions like the formation of protein-based droplets or hydrogels	multivalent SH3-binding motifs in phase separation, granule-like assemblies of RNA-binding proteins containing low-complexity IDRs, mucins
	biomineralization117,341		structural disorder is common in proteins with roles in biomineralization, such as the formation of bone and teeth	caseins, osteopontin, bone sialoprotein 2, dentin sialophosphoprotein