WT PTEN and each mutant

WT PTEN and each mutant PTEN structure associated and also correlates with protein-protein interaction hot- with ASD and/or cancer (Figures 2A–2D and S2A–S2D). spots.70 We define the core residues as those residing at
˚ depths greater than 4A, in accordance with previous work.71
Comparison of the depth distribution of ASD-associated mutations (c.69A>C [p.Leu23Phe], c.194A>G [p.Tyr65Cys], c.202T>C [p.Tyr68His], c.302T>C [p.Ile101Thr], c.365T>G [p.Ile122Ser], and c.658C>G [p.Leu220Val]) demonstrates low connectivity with surface residues when com-pared to WT PTEN (Figure 2A). Cancer-associated muta-tions (c.71A>G [p.Asp24Gly], c.275A>C [p.Asp92Ala], c.388C>G [p.Arg130Gly], c.401T>G [p.Met134Arg], c.613A>G [p.Met205Val], and c.1033C>G [p.Leu345Val]) demonstrate stronger connectivity for core residues, high-lighting them as critical hubs for signal propagation (Figure 2B). Moreover, we see a notable loss of surface-resi-due interactions, further demonstrating that the core resi-dues are key players in PTEN structural communication. The mean difference between the core and surface connec-tivity was larger among cancer-associated variants; how-ever, this difference was not statistically significant (p ¼ 0.31). Additionally, when we compared area under the curve (AUC) distributions across phenotype categories, there were no statistically significant differences. We also observed a loss in connectivity of the surface residues for variants that occur in individuals with ASD, as well as unre-lated individuals with cancer (but with no single individual having both ASD and cancer) when compared to either var-iants associated only with ASD or variants associated only with cancer (Figure 2C). The PTEN c.509G>T (p.Ser170Ile) CORM-3 associated with concurrent ASD and cancer phe-notypes in a single individual showed effects similar to cancer (only) variants (Figure 2D). Though the high RD of cancer-associated variants reveals potential regions (P loop, residues 123–131; motif 1, residues 169–180; and CBR3 loop, residues 260–269) prone to mediate allosteric ef-fects, no significant differences were seen when compared to ASD-associated variants (Figures S2A–S2D). Overall, our results demonstrate that in comparison to ASD-associated variants, cancer-associated variants demonstrate stronger connectivity for core residues, identifying them as critical hubs for signal propagation. Additionally, we see a loss of surface-residue interactions, further demonstrating that the core residues are key players in PTEN structural commu-nication and underscoring the extent to which the cancer-associated RIN is perturbed at long distances.
Structural Communication in PTEN’s Inter-domain Region Influences Heightened Allosteric Communications Specific to Cancer
In order to further distinguish critical residue hubs that play a key role in potential allosteric regulation and long-range structural communication, we computed two critical, quantitative-centrality network parameters, betweenness and closeness centrality. Nodes with high betweenness values control the flow of topological infor-mation in a network,72 whereas nodes with high closeness values play a principal part in the transmission of informa-tion to all other residues in the network.57 Nodes with
large betweenness and closeness values have been shown to lie in critical regions in proteins, and they are typically binding free energy hotspots or located in the vicinity of hotspots.24,31,64,73 We therefore posit that allosteric communication is effectively propagated by way of highly conserved residues that are within the active site and inter-domain region and that exhibit a significantly higher betweenness compared to the network average. Moreover, our recent studies reveal these regions are prone to muta-tions that thermodynamically destabilize the structure.22