LiteFold/DisProt huggingface dataset:
Protein: DP04298 (UniProt Q13546)
Region: residues 300	to 560
Annotation: disorder (Structural state)
Evidence: author inference based on intrinsic disorder prediction used in manual assertion
Supporting statements:
We investigated why RIP1/3-RHIM and RIP1/3-FL could form such large complexes. Secondary structure predictions suggested that the region between the KD and the DD in RIP1 (~residues 300–560) and the region C-terminal to the KD in RIP3 (~residues 300-end) are mostly unstructured random coils (Rost et al., 2004).
Protein: DP04298 (UniProt Q13546)
Region: residues 496	to 531
Annotation: disorder (Structural state)
Evidence: nuclear magnetic resonance spectroscopy evidence used in manual assertion
Supporting statements:
Using the mapped amyloid core sequences (Figures 1B and ​and3A)3A) as targets, the majority of the peaks in the NCA spectrum were assigned, with 16 residues of RIP1 (T532–Y544 and Y546–E548) and 6 consecutive residues of RIP3 (G457–D462) (Figures 3C and 3D).
The spectra recorded with cross-polarization (CP)-based solid-state NMR above 0°C can be explained by ~37 resolved residues. Most of the residues outside the β-amyloid core were unobserved and either too dynamic or disordered to be visible in these spectra.
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Protein: DP04298 (UniProt Q13546)
Region: residues 549	to 583
Annotation: disorder (Structural state)
Evidence: nuclear magnetic resonance spectroscopy evidence used in manual assertion
Supporting statements:
Using the mapped amyloid core sequences (Figures 1B and ​and3A)3A) as targets, the majority of the peaks in the NCA spectrum were assigned, with 16 residues of RIP1 (T532–Y544 and Y546–E548) and 6 consecutive residues of RIP3 (G457–D462) (Figures 3C and 3D).
The spectra recorded with cross-polarization (CP)-based solid-state NMR above 0°C can be explained by ~37 resolved residues. Most of the residues outside the β-amyloid core were unobserved and either too dynamic or disordered to be visible in these spectra.
Protein: DP04298 (UniProt Q13546)
Region: residues 496	to 583
Annotation: amyloid fibril formation (Biological process)
Evidence: electron microscopy evidence used in manual assertion
Supporting statements:
Upon limited proteolysis to remove the flanking domains by subtilisin, the same enzyme used in the nuclear magnetic resonance (NMR) sample preparation (see section “Amyloid Core of the RIP1/RIP3 Complex”), clear fibril structures were revealed for RIP1/3-FL, similar to RIP1/3-RHIM (Figure 1D).
Protein: DP04298 (UniProt Q13546)
Region: residues 525	to 555
Annotation: protein serine/threonine kinase binding (Molecular function)
Evidence: bait-prey hybrid interaction evidence used in manual assertion
Supporting statements:
His-tag pull-down experiments of the coexpression constructs showed that the interaction was retained, even when RIP1 was only 31 residues (525–555) and RIP3 was only 19 residues (446–464) in length (Figures 3A, S3A, and S3B).
Protein: DP04298 (UniProt Q13546)
Region: residues 532	to 548
Annotation: protein serine/threonine kinase binding (Molecular function)
Evidence: nuclear magnetic resonance spectroscopy evidence used in manual assertion
Supporting statements:
To further elucidate the core size and the secondary structure of the RIP1/RIP3 complex, we used solid-state NMR.
Using the mapped amyloid core sequences (Figures 1B and ​and3A)3A) as targets, the majority of the peaks in the NCA spectrum were assigned, with 16 residues of RIP1 (T532–Y544 and Y546–E548) and 6 consecutive residues of RIP3 (G457–D462) (Figures 3C and 3D).
Protein: DP04298 (UniProt Q13546)
Region: residues 532	to 549
Annotation: order (Structural state)
Evidence: nuclear magnetic resonance spectroscopy evidence used in manual assertion
Supporting statements:
Using the mapped amyloid core sequences (Figures 1B and ​and3A)3A) as targets, the majority of the peaks in the NCA spectrum were assigned, with 16 residues of RIP1 (T532–Y544 and Y546–E548) and 6 consecutive residues of RIP3 (G457–D462) (Figures 3C and 3D).
Negative and positive values of the difference in secondary chemical shifts between Cα and Cβ (i.e., ΔδCα-ΔδCβ or δCα for Gly) are indicative of β sheet and α-helical conformations, respectively. Most of the residues in the amyloid core are compatible with β sheet conformations, and the 4 central RHIM residues show consecutive negative shift differences (Figures 3D and S3E).
(D) Plot of the difference in secondary chemical shift between Cα and Cβ, indicative of secondary structures (only ΔδCα for Gly).
Protein: DP04298 (UniProt Q13546)
Region: residues 532	to 549
Annotation: disorder to order (Structural transition)
Evidence: nuclear magnetic resonance spectroscopy evidence used in manual assertion
Supporting statements:
Using the mapped amyloid core sequences (Figures 1B and ​and3A)3A) as targets, the majority of the peaks in the NCA spectrum were assigned, with 16 residues of RIP1 (T532–Y544 and Y546–E548) and 6 consecutive residues of RIP3 (G457–D462) (Figures 3C and 3D).
Negative and positive values of the difference in secondary chemical shifts between Cα and Cβ (i.e., ΔδCα-ΔδCβ or δCα for Gly) are indicative of β sheet and α-helical conformations, respectively. Most of the residues in the amyloid core are compatible with β sheet conformations, and the 4 central RHIM residues show consecutive negative shift differences (Figures 3D and S3E).
(D) Plot of the difference in secondary chemical shift between Cα and Cβ, indicative of secondary structures (only ΔδCα for Gly).
Protein: DP04298 (UniProt Q13546)
Region: residues 496	to 583
Annotation: amyloid fibril formation (Biological process)
Evidence: far-UV circular dichroism evidence used in manual assertion
Supporting statements:
The RIP1 and RIP3 CD spectra showed similar secondary structures as the RIP1/RIP3 complex, and ThT fluorescence and CR absorption confirmed their amyloidal structures (Figure S4). EM of negatively stained RIP1 and RIP3 samples revealed that the homocomplexes are able to form fibrils by themselves as well (Figure 4B). However, these fibrils appeared to be less regular and shorter than those of the RIP1/RIP3 heterocomplex (Figure 1D).
Protein: DP04298 (UniProt Q13546)
Region: residues 496	to 583
Annotation: identical protein binding (Molecular function)
Evidence: far-UV circular dichroism evidence used in manual assertion
Supporting statements:
The RIP1 and RIP3 CD spectra showed similar secondary structures as the RIP1/RIP3 complex, and ThT fluorescence and CR absorption confirmed their amyloidal structures (Figure S4). EM of negatively stained RIP1 and RIP3 samples revealed that the homocomplexes are able to form fibrils by themselves as well (Figure 4B). However, these fibrils appeared to be less regular and shorter than those of the RIP1/RIP3 heterocomplex (Figure 1D).
Protein: DP04298 (UniProt Q13546)
Region: residues 496	to 583
Annotation: identical protein binding (Molecular function)
Evidence: thioflavin T based fluorescence spectroscopy evidence
Supporting statements:
The RIP1 and RIP3 CD spectra showed similar secondary structures as the RIP1/RIP3 complex, and ThT fluorescence and CR absorption confirmed their amyloidal structures (Figure S4). EM of negatively stained RIP1 and RIP3 samples revealed that the homocomplexes are able to form fibrils by themselves as well (Figure 4B). However, these fibrils appeared to be less regular and shorter than those of the RIP1/RIP3 heterocomplex (Figure 1D).
Protein: DP04298 (UniProt Q13546)
Region: residues 496	to 583
Annotation: amyloid fibril formation (Biological process)
Evidence: thioflavin T based fluorescence spectroscopy evidence
Supporting statements:
The RIP1 and RIP3 CD spectra showed similar secondary structures as the RIP1/RIP3 complex, and ThT fluorescence and CR absorption confirmed their amyloidal structures (Figure S4). EM of negatively stained RIP1 and RIP3 samples revealed that the homocomplexes are able to form fibrils by themselves as well (Figure 4B). However, these fibrils appeared to be less regular and shorter than those of the RIP1/RIP3 heterocomplex (Figure 1D).
Protein: DP04298 (UniProt Q13546)
Region: residues 496	to 583
Annotation: amyloid fibril formation (Biological process)
Evidence: Fourier-transform infrared spectroscopy evidence used in manual assertion
Supporting statements:
(E) Superimposed Fourier transform infrared spectra of RIP/RIP3-RHIM (magenta) and the I539D mutant of RIP1 (cyan). Only the WT RIP1/RIP3 complexes, not the RHIM mutant, showed the amide I’ maxima at 1,623 cm−1 (dashed vertical red line), which is characteristic of β-amyloid.
Protein: DP04298 (UniProt Q13546)
Region: residues 539	to 545
Annotation: necroptotic process (Biological process)
Evidence: loss-of-function mutant phenotype evidence used in manual assertion
Supporting statements:
Like the RHIM AAAA mutant, the RIP1 mutants I539P, I541P, and N545P were much weaker in mediating necrosis than WT RIP1 (Figure 7D), recapitulating the in vitro interaction data.
Thus, these results define a critical role for RHIM-mediated amyloidal RIP1/RIP3 fibrils in the activation of RIP1/RIP3 kinase activity and the induction of programmed necrosis.
Protein: DP04298 (UniProt Q13546)
Region: residues 539	to 545
Annotation: activation of protein kinase activity (Biological process)
Evidence: loss-of-function mutant phenotype evidence used in manual assertion
Supporting statements:
All three RIP1 mutants, I539P, I541P, and N545P, showed defective kinase activation (Figure 7E).
Thus, these results define a critical role for RHIM-mediated amyloidal RIP1/RIP3 fibrils in the activation of RIP1/RIP3 kinase activity and the induction of programmed necrosis.
Protein: DP04298 (UniProt Q13546)
Region: residues 539	to 545
Annotation: ripoptosome assembly involved in necroptotic process (Biological process)
Evidence: loss-of-function mutant phenotype evidence used in manual assertion
Supporting statements:
Clustering of RIP1 and RIP3 into punctate-like structures is a distinct feature of necrosis (Figures S6B–S6D). This was confirmed by immunogold EM (Figure 6F). When HeLa cells, which do not express endogenous RIP3, were transfected with RIP3-mCherry and stimulated with TNF, zVAD-fmk, and LBW242 to induce necrosis, they showed complete overlap of ThT staining with RIP3-mCherry puncta (Figure 6G).
Similar defects in clustering in mutations within the core RHIM residues were observed with truncated RIP1 (residues 496–583) and RIP3 (residues 388–518) lacking the KDs and DD (Figure S7B).
Spontaneous assembly of RIP1-RHIM and RIP3-RHIM fibrils in vivo requires an intact RHIM. The indicated wild-type and mutant RIP1-CFP and/or RIP3-YFP plasmids were expressed in RIP3/ fibroblasts by transfection.
Mutations within the RHIM core disrupted the spontaneous assembly of these filaments in the truncation RHIM proteins.
Protein: DP04299 (UniProt O43353)
Region: residues 173	to 183
Annotation: disorder (Structural state)
Evidence: X-ray crystallography-based structural model with missing residue coordinates used in manual assertion
Supporting statements:
Both the RIP2K-AMPPCP and RIP2KD146N structures exhibit a disordered AS. Only residues 164–172 and 186–196 could be traced for RIP2K-AMPPCP chain B (S4 Fig), implying that there is no electron density for any of the phosphorylation sites detected by mass spectrometry.
Cross-references: PDB:5NG0
Protein: DP04299 (UniProt O43353)
Region: residues 519	to 540
Annotation: disorder (Structural state)
Evidence: cryogenic electron microscopy-based structural model with missing residue coordinates used in manual assertion
Supporting statements:
Interestingly H6 is absent in both the crystal and NMR structures and replaced by a long C-terminal loop, visible only in the NMR structure, which contains putative phosphorylation sites41–43.
Cross-references: EMDB:4399
PDB:6GGS
Protein: DP04299 (UniProt O43353)
Region: residues 512	to 540
Annotation: disorder (Structural state)
Evidence: nuclear magnetic resonance spectroscopy evidence used in manual assertion
Supporting statements:
Relying on the distribution of the respective amino acid types in the sequence, this strongly suggests that the missing signals concern residues in the C-terminal segment from 512 to 540. Especially the absence of three proline signal sets, only one being detected, indicates strong structural heterogeneity or mobility in that region where they cluster.
We were not able to assign any cross-peaks to the C-terminal 29 residues that were reported to be flexible by solution NMR investigations40. 
Cross-references: BMRB:27555
Protein: DP04300 (UniProt Q9UBB9)
Region: residues 1	to 350
Annotation: disorder (Structural state)
Evidence: far-UV circular dichroism evidence used in manual assertion
Supporting statements:
First, the far-UV CD signature of the protein in 200 mM NaCl (Fig. 7), providing secondary structure information, is characteristic of random coil with a strong negative band at 205 nm. The very weak positive band between 195 and 200 nm further demonstrates for the first time at experimental level that the human TFIP11 N-TER is mainly disordered.
Protein: DP04300 (UniProt Q9UBB9)
Region: residues 1	to 350
Annotation: disorder (Structural state)
Evidence: fluorescence evidence used in manual assertion
Supporting statements:
ITF data are in agreement with MD simulations, pointing out that the conformational ensemble of TFIP11 N-TER is more disordered in 200 mM than in 0 mM NaCl, due to the maximisation of electrostatic interactions with the ions in solution.
Protein: DP04300 (UniProt Q9UBB9)
Region: residues 1	to 350
Annotation: order to disorder (Structural transition)
Evidence: fluorescence evidence used in manual assertion
Supporting statements:
ITF data are in agreement with MD simulations, pointing out that the conformational ensemble of TFIP11 N-TER is more disordered in 200 mM than in 0 mM NaCl, due to the maximisation of electrostatic interactions with the ions in solution. This indicates a conformational dynamic where the state of Trp residues can vary from fully exposed to more buried depending on the environment.
Protein: DP04300 (UniProt Q9UBB9)
Region: residues 1	to 350
Annotation: disorder (Structural state)
Evidence: author inference based on intrinsic disorder prediction used in manual assertion
Supporting statements:
The three IDRs are located at the N-TER region and are separated by shorter flexible segments for which the disorder score varies between 0.2 and 0.5. The first disordered region (IDR1) is comprised between residues 1 and 50 and is followed by two longer disordered regions comprising residues 85–145 (IDR2) and 190–265 (IDR3). Due to a much larger variability amongst the predictors for the residues comprised between the position 270 and 350, we restrain to assign this segment as an IDR. Nevertheless, scores close to the 0.5 threshold indicate that a large flexibility is still present in this region.
The TFIP11 N-TER region displays both low mean net charge and hydropathy and is found above the boundary defined by the equation <R ≥ 2.785<H > − 1.15, i.e. clearly laying in the IDP area, strongly supporting the assignation of the N-TER domain as a mainly disordered one.
Protein: DP04300 (UniProt Q9UBB9)
Region: residues 1	to 350
Annotation: order to disorder (Structural transition)
Evidence: far-UV circular dichroism evidence used in manual assertion
Supporting statements:
First, the far-UV CD signature of the protein in 200 mM NaCl (Fig. 7), providing secondary structure information, is characteristic of random coil with a strong negative band at 205 nm. The very weak positive band between 195 and 200 nm further demonstrates for the first time at experimental level that the human TFIP11 N-TER is mainly disordered.
In 0 mM NaCl, a significant change is observed in the CD spectrum revealing two broad negative bands at 220 and 226 nm, as well as a broad positive band centred at 199 nm, indicating a significant decrease in the disorder content to give a predominance of ß-sheets.
Interestingly, the CD footprint observed at 0 mM NaCl shows an enrichment in ß-sheets, suggesting an amyloid-like fibrillation of the protein, as already observed for various IDPs which are prone to aggregate [66,67].
Protein: DP04300 (UniProt Q9UBB9)
Region: residues 1	to 350
Annotation: amyloid-beta formation (Biological process)
Evidence: combinatorial experimental and author inference evidence used in manual assertion
Supporting statements:
Interestingly, the CD footprint observed at 0 mM NaCl shows an enrichment in ß-sheets, suggesting an amyloid-like fibrillation of the protein, as already observed for various IDPs which are prone to aggregate [66,67].
Interestingly, a second band appears at 470 nm, which is most likely associated to deep-blue autofluorescence (dbAF), an intrinsic fluorescence mainly found in proteins forming amyloid fibrils [70].
Nevertheless, the presence of such dbAF signal, in conjunction with the main ß-sheet CD signature, suggests that in the absence of salt, TFIP11 N-TER might tend to assemble into stable aggregates and adopt more ordered structures.
Protein: DP04301 (UniProt Q75PQ8)
Region: residues 1	to 10
Annotation: disorder (Structural state)
Evidence: X-ray crystallography-based structural model with missing residue coordinates used in manual assertion
Supporting statements:
We anticipate that these interactions flexibly tether ORCA to ORC since the N‐terminal Orc2 region is predicted to be disordered and not visible in prior ORC structures (Jaremko et al, 2020; Schmidt & Bleichert, 2020).
This region is not visible in the structure.
Cross-references: PDB:8SIU
Protein: DP04301 (UniProt Q75PQ8)
Region: residues 29	to 100
Annotation: disorder (Structural state)
Evidence: X-ray crystallography-based structural model with missing residue coordinates used in manual assertion
Supporting statements:
We anticipate that these interactions flexibly tether ORCA to ORC since the N‐terminal Orc2 region is predicted to be disordered and not visible in prior ORC structures (Jaremko et al, 2020; Schmidt & Bleichert, 2020).
This region is not visible in the structure.
Cross-references: PDB:8SIU
Protein: DP04302 (UniProt P06897)
Region: residues 120	to 130
Annotation: disorder (Structural state)
Evidence: cryogenic electron microscopy-based structural model with missing residue coordinates used in manual assertion
Supporting statements:
This region is not visible in the structure.
Cross-references: PDB:8SIY
Protein: DP04304 (UniProt Q8I0V0)
Region: residues 218	to 222
Annotation: self proteolysis (Biological process)
Evidence: x-ray crystallography evidence used in manual assertion
Supporting statements:
Another common feature is that the PD had undergone autocleavage at its primary maturation site (Asp 217 in PfS1FL and Asp202 in PvS1FL) but remained tightly associated to the catalytic core in the crystal, partially occupying the active site.
Cross-references: PDB:8POL
Protein: DP04304 (UniProt Q8I0V0)
Region: residues 218	to 329
Annotation: flexible N-terminal tail (Disorder function)
Evidence: x-ray crystallography evidence used in manual assertion
Supporting statements:
Another common feature is that the PD had undergone autocleavage at its primary maturation site (Asp 217 in PfS1FL and Asp202 in PvS1FL) but remained tightly associated to the catalytic core in the crystal, partially occupying the active site.
The PD connecting segment between the two subunits (residues 116–153) and the N-terminal region of the mature catalytic domain (residues 236–347) are not visible in the electron density and are presumably disordered in the crystals.
After the auto autocleavage at its Asp 217, this region becomes the flexible N-terminal tail of the mature catalytic domain.
Cross-references: PDB:8POL
Protein: DP04306 (UniProt Q8I384)
Region: residues 72	to 153
Annotation: disorder (Structural state)
Evidence: X-ray crystallography-based structural model with missing residue coordinates used in manual assertion
Supporting statements:
While the 11-residue insert in loop L8 is well ordered, the 74 residue LCR insert in loop L2 is largely disordered: only the flanking residues D70-N71 and C154-N158 are modeled into visible electron density, and C154 is refined with half occupancy. 
Cross-references: PDB:3MMR
Protein: DP04308 (UniProt P43586)
Region: residues 1	to 204
Annotation: disorder (Structural state)
Evidence: nuclear magnetic resonance spectroscopy evidence used in manual assertion
Supporting statements:
The spectrum showed poor signal dispersion, confirming that Loc1p is largely unstructured in the absence of a binding partner.
Protein: DP04308 (UniProt P43586)
Region: residues 1	to 14
Annotation: RNA binding (Molecular function)
Evidence: protein-oligonucleotide microarray binding evidence used in manual assertion
Supporting statements:
We identified eight short, positively charged, unfolded nucleic acid binding (PUN) motifs in Loc1p, which cooperatively act as potent RNA annealers.
Protein: DP04308 (UniProt P43586)
Region: residues 39	to 47
Annotation: RNA binding (Molecular function)
Evidence: protein-oligonucleotide microarray binding evidence used in manual assertion
Supporting statements:
We identified eight short, positively charged, unfolded nucleic acid binding (PUN) motifs in Loc1p, which cooperatively act as potent RNA annealers.
Protein: DP04308 (UniProt P43586)
Region: residues 63	to 69
Annotation: RNA binding (Molecular function)
Evidence: protein-oligonucleotide microarray binding evidence used in manual assertion
Supporting statements:
We identified eight short, positively charged, unfolded nucleic acid binding (PUN) motifs in Loc1p, which cooperatively act as potent RNA annealers.
Protein: DP04308 (UniProt P43586)
Region: residues 89	to 95
Annotation: RNA binding (Molecular function)
Evidence: protein-oligonucleotide microarray binding evidence used in manual assertion
Supporting statements:
We identified eight short, positively charged, unfolded nucleic acid binding (PUN) motifs in Loc1p, which cooperatively act as potent RNA annealers.
Protein: DP04308 (UniProt P43586)
Region: residues 137	to 147
Annotation: RNA binding (Molecular function)
Evidence: protein-oligonucleotide microarray binding evidence used in manual assertion
Supporting statements:
We identified eight short, positively charged, unfolded nucleic acid binding (PUN) motifs in Loc1p, which cooperatively act as potent RNA annealers.
Protein: DP04308 (UniProt P43586)
Region: residues 154	to 165
Annotation: RNA binding (Molecular function)
Evidence: protein-oligonucleotide microarray binding evidence used in manual assertion
Supporting statements:
We identified eight short, positively charged, unfolded nucleic acid binding (PUN) motifs in Loc1p, which cooperatively act as potent RNA annealers.
Protein: DP04308 (UniProt P43586)
Region: residues 170	to 178
Annotation: RNA binding (Molecular function)
Evidence: protein-oligonucleotide microarray binding evidence used in manual assertion
Supporting statements:
We identified eight short, positively charged, unfolded nucleic acid binding (PUN) motifs in Loc1p, which cooperatively act as potent RNA annealers.
Protein: DP04308 (UniProt P43586)
Region: residues 191	to 199
Annotation: RNA binding (Molecular function)
Evidence: protein-oligonucleotide microarray binding evidence used in manual assertion
Supporting statements:
We identified eight short, positively charged, unfolded nucleic acid binding (PUN) motifs in Loc1p, which cooperatively act as potent RNA annealers.