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dSysMap: exploring the edgetic role of disease mutations

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Figure 1: The dSysMap resource.

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Acknowledgements

This work was partially supported by the European commission through the SyStemAge project (agreement no. 306240) and the European Research Council through the SysPharmAD grant (agreement no. 201014).

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Correspondence to Patrick Aloy.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Enrichment of mutated surface residues on known interaction interfaces.

The table shows the contingency matrix of surface residues on the structure of human proteins that are mutated in human diseases and belong (or not) to interaction interfaces. Mutated residues on the surface of proteins are more likely to be located at known interaction interfaces. The enrichment is calculated aswhile the log odds ratio is calculated asThe P-value is calculated with a Fisher's exact test on the contingency matrix. Standard error is calculated aswhere A, B, C, D are the corresponding numbers of the contingency matrix (A and B in the first row, C and D in the second).

Supplementary Figure 2 Effects of mutations on the same protein but on different interaction interfaces and mutations on different proteins but on the two sides of the same interaction interface.

(a) The table shows the number of pairs of mutations, on interaction interfaces of the same protein, that are causing different phenotypes and can be found on interfaces mediated different interactions vs. those that mediated the same interaction. Pairs of mutations on the same proteins but on interfaces mediating different interactions are more likely to cause different phenotypes. (b) The table shows the number of pairs of mutations, on interacting proteins that are causing the same phenotype and can be found on the two sides of the same interfaces vs. those that are on interfaces mediating other interactions. Pairs of mutations on different but interacting proteins that are on opposite sides of the same interface are more likely to cause the same phenotype than pairs of mutations that are on different non interacting interfaces. The different quantities are calculated as detailed in the legend of Supplementary Figure 1.

Supplementary Figure 3 Schematic case of an edgetic effect.

Mutations S and T display an edgetic effect on the interaction neighborhood of protein P. (a) While normally P interacts with X, Y and Z, in the presence of mutation S (b), located on the interface of the P-X interaction (but not overlapping with the P-Y and P-Z interfaces), the interaction with X is lost while the other two are preserved. (c) Mutation T, instead, being at the P-Y interface selectively affects the corresponding interaction, while leaving unaltered the other two.

Supplementary Figure 4 Experimentally tested cases.

Every row represents one of the 5 cases that were tested. The first column shows the interactions that were tested and the mutations that can be smapped to the interaction interfaces (small magenta circles). The remaining three columns represent the experimental results. Solid lines represent interactions that could be detected in our Y2H screen. Dashed lines represent wild-type interactions that, although not identified in the Y2H screen, are supported either by crystallographic structures or by other experimental evidence (for example, the CASK-PLK2 interaction is confirmed by a Y2H experiment [Wang et al, Mol Sys Biol 7, 536 (2011)], as deposited in Intact [Kerrien et al, Nucleic Acids Res 40, D841 (2012)], IMEx interaction ID IM-15364-946). Please notice that in some of the cases interactions can be found on an interface that mediate more than one interaction, like for CASK, where the Y268H mutation is predicted to be at the interface with both CDK9 and PLK2 and, therefore, might affect both interactions. See the supplementary text for a description of each case. Nature

Supplementary Figure 5 Validation of edgetic perturbations.

(a) The Y268H mutation on CASK is located at the interface between CASK and CDK9 but is far from the interface with PRKD2. Both interactions are likely to happen through the kinase domain even if they are mediated by different interfaces. Consistently the CASKY268H retains the CASK-PRKD2 interaction but looses the interaction with CDK9. The CASK-CDK9 interaction is modeled after the kinase-kinase domain-domain structural template PDB ID 2wnt_A:B obtained from 3did [Mosca et al, Nucleic Acids Res 42, D374 (2914)], while CASK-PRKD2 interaction is modeled after the template PDB ID 3gok_K:H. (b) Both the ETFA-T266M and the ETFBR164Q mutants loose their ability to dimerize. The ETFB-R164Q mutant maintains its interaction with ACADM. As a matter of fact, the ETFB-R164Q mutation is mapped to a region in the structure of the ETFB-ACADM interaction (PDB ID 2a1t_D:S) that is far from their binding interface, while both T266M and R164Q mutations can be mapped on the binding interface of the ETFA-ETFB dimer (PDB ID 1efv_A:B). (c) The G31A and D132A mutations on EXOSC3 selectively disrupt its interactions with EXOSC5 and EXOSC9 but do not affect its ability to interact with EXOSC1. The different components are highlighted in the structure of the human RNA exosome (PDB ID 2nn6). Two separate views show (1) the interaction of EXOSC3 (pink, chain G) with EXOSC5 (light orange, chain D) and EXOSC9 (purple, chain A) and (2) the interaction of EXOSC3 with EXOSC1 (dark gray, chain I). The G31A mutation is located on the EXOSC3-EXOSC5 interface, while the D132A mutation is located on the EXOSC3-EXOSC9 interface. Both mutations are far from the EXOSC3-EXOSC1 interface.

Supplementary Figure 6 Disease map associated with the Loeys-Dietz syndrome and connected disease phenotypes.

The disease map associated to the Loeys-Dietz syndrome (LDS) is an example of annotated network reported by dSysMap (f). The network represents the proteins affected by mutations related to LDS and their first interactors. Different colors for the nodes and edges represent the different types of structural information available for proteins and interactions as detailed in the legend. Small colored circles on the edges and proteins represent mutations mapped on proteins and interactions. Three cases are enlarged from the network. (a) Interaction neighborhood of TGFBR1 (corresponding to the orange shaded circle in the network); structures are available for the kinase and the activin receptor domains. Mutated residues are shown in spheres-representation and colored based on their structural classification (black for buried residues, blue for surface residues and red for interface residues). The Activin receptor domain mediates the interactions with TGFB1, TGFB3 and TGFBR2. The kinase domain mediates the TGFBR1 homomeric interaction, the interaction with FKBP1A and is predicted to mediate the interaction with BMPR2. Red circles highlight the mutations that affect every interaction. (b) Interaction neighborhood of ACVR1 (corresponding to the gray shaded circle in the network). Mutations related to Fibrodysplasia ossificans progressive are located at the ACVR1 homodimeric interface, at the interface with FKBP1A and at the predicted interface with BMPR2 but not at the interface of the homology model for the ACVR1-TGFBR2 interaction. (c) Interaction neighborhood of SMAD3 (corresponding to the pink shaded oval in the network). Mutations for LDS on SMAD3 are found at the interface with SMAD4 (d). Also mutations for Juvenile polyposis syndrome on SMAD4 are found at the interface with SMAD3, even if on a different structural model (e).

Supplementary information

Supplementary Figures and Text

Supplementary Figures 1–6, Supplementary Tables 1, 3, 4 and 7, and Supplementary Notes 1–5 (PDF 2591 kb)

Supplementary Table 2

Enrichment of mutations on interaction selected for testing (XLSX 13 kb)

Supplementary Table 5

Results of the Y2H screen (XLSX 14 kb)

Supplementary Table 6

Autoactivating baits (XLSX 10 kb)

Supplementary Table 8

PDB files of the single proteins used for the analysis of the disease map of Loeys-Dietz syndrome and the preparation of Supplementary Figure 6 (XLSX 16 kb)

Supplementary Table 9

PDB files of the interactions used for the analysis of the disease map of Loeys-Dietz syndrome and the preparation of Supplementary Figure 6 (XLSX 19 kb)

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Mosca, R., Tenorio-Laranga, J., Olivella, R. et al. dSysMap: exploring the edgetic role of disease mutations. Nat Methods 12, 167–168 (2015). https://doi.org/10.1038/nmeth.3289

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