Figure 1.
Representation of PIN,SPIN and iSPIN.
In A) proteins in PIN are represented; the ones colored black have PDB IDs and the ones colored blue do not have PDB IDs. In B) The proteins with PDB ID and interactions among them constitutes SPIN. In C) The proteins with PDB ID and protein interface information and their interactions constitutes iSPIN. The zoomed representations give idea about what type of information each network contains; PIN is an abstract representation of interactions, SPIN is a subset of PIN with information of PDB IDs, and iSPIN contains the most detailed information including protein interfaces into network. All the networks are visualized using Cytoscape [76].
Table 1.
The number of proteins and interactions in each network.
Table 2.
Average interface properties of cancer and non-cancer interactions. ± in brackets refers to standard deviation.
Table 3.
Average interface properties of hub and nonhub involved interactions. ± in brackets refers to standard deviation. The first and second lines in p-value column represent the comparison of hub/non-hub and single-interface hub/non-hub interactions, respectively.
Table 4.
Cancer/noncancer classification analysis and statistical test results for iSPIN interface data, iSPIN clustered data according to phenotype, molecular function or biological process. In the first column, cr stands for cancer-related interfaces and ncr stands for noncancer interfaces. The second column gives the classification performances; first line is accuracy and second line is weighted precision value. The third column lists features (mean values, standard deviations) used in classification for cancer and noncancer interfaces. The last column is the significance of mean values and standard deviations.
Figure 2.
Topological properties of SPIN.
(A) Degree distribution of proteins, R2 = 0.914 for power law fit (B) Average clustering coefficient (C) Topological coefficients (D) Shortest path length distribution.
Table 5.
Network parameters calculated for each network.
Figure 3.
Molecular function and biological process distribution of cancer & non-cancer genes.
(A) Molecular distribution of genes in SPIN (B) Molecular distribution of genes in PIN (C) Biological process distribution in SPIN (D) Biological process distribution in PIN.
Figure 4.
SPIN is clustered into sub-networks, proteins are classified into four categories; cancer-hub, noncancer-hub, cancer-nonhub, noncancer-nonhub are displayed in purple, green, blue and white color, respectively. Over-represented molecular functions (if any) are shown for each sub-network.
Figure 5.
Essentiality of different categories of proteins.
A) Essentiality in PIN. B) Essentiality in SPIN. C) Essentiality in random network.
Figure 6.
Essentiality of proteins classified as cancer-hub, cancer-nonhub and non-cancer-hub in SPIN, PIN and random network.
Table 6.
Correspondence of HB, H-NB to Multi/single interface proteins and Essentiality % in cancer/noncancer & Multi/single interface proteins HB and H-NB refer to hub-bottlenecks and hub-nonbottlenecks, respectively.
Figure 7.
The nodes colored in green and red are multi-interface hubs and single-interface hubs, respectively. In the zoomed representation, the interactions of a multi-interface hub; ERBB3 is displayed.
Figure 8.
Representation of ERBB3-NRG1 interaction schematically.
The interactions are visualised using VMD [78] A) ERBB3 (1m6b_A) and NRG1 (1hae_A) are shown as newcartoon diagram in blue and red color, respectively. The transparent surface represents the interface region. The labeled residues (represented by their Cα atoms) of 1hae_A are reported to be critical for binding in a previous work [58]; i.e. when they are mutated to alanine, the binding affinity for ERBB3 was significantly reduced. B) HER3 (blue) – pertuzumab heavy chain (yellow) is shown. Pertuzumab shares the same interface with NRG1 (see “An inhibitor affecting Erb signaling pathway: pertuzumab” section).
Figure 9.
Ribbon diagram and interface representation of ERBB3 interactions with PLCG1, EPOR and ACK1.
ERBB3 (1m6b_A), PCLG1 (1hsq_A), EPOR (1eer_B) and ACK1 (1u46_A) are colored in blue, red, pink and orange respectively. Interface residues are shown as spheres. (A) ERBB3-PLCG1 interaction. (B) ERBB3-EPOR interaction. (C) ERBB3-ACK1 interaction.
Figure 10.
Ribbon diagram and interface representation of RAF1 interactions with YWHAZ, MAP2K2 and CDC25A.
RAF1 (1c1y_B), YWHAZ (1qja_A), MAP2K2 (1s9i_A) and CDC25A (1c25_A) are colored in blue, red, cyan and purple respectively. (A) RAF1-YWHAZ interaction. (B) RAF1-MAP2K2 interaction. (C) RAF1-CDC25A interaction. Interaction interfaces of RAF1 through YWHAZ, MAP2K2 and CDC25A are highly overlapping; the interactions are mutually exclusive.
Figure 11.
Flowchart representation of the method of mapping interactions to 3D structures and generating iSPIN.
The method is applied for all the interactions in the human interactome (PIN).