Conformational Dynamics and Allosteric Regulation Landscapes of Germline PTEN Mutations Associated with Autism Compared to Those Associated with Cancer

Abstract

Individuals with germline PTEN tumor-suppressor variants have PTEN hamartoma tumor syndrome (PHTS). Clinically, PHTS has variable presentations; there are distinct subsets of PHTS-affected individuals, such as those diagnosed with autism spectrum disorder (ASD) or cancer. It remains unclear why mutations in one gene can lead to such seemingly disparate phenotypes. Therefore, we sought to determine whether it is possible to predict a given PHTS-affected individual's a priori risk of ASD, cancer, or the co-occurrence of both phenotypes. By integrating network proximity analysis performed on the human interactome, molecular simulations, and residue-interaction networks, we demonstrate the role of conformational dynamics in the structural communication and long-range allosteric regulation of germline PTEN variants associated with ASD or cancer. We show that the PTEN interactome shares significant overlap with the ASD and cancer interactomes, providing network-based evidence that PTEN is a crucial player in the biology of both disorders. Importantly, this finding suggests that a germline PTEN variant might perturb the ASD or cancer networks differently, thus favoring one disease outcome at any one time. Furthermore, protein-dynamic structural-network analysis reveals small-world structural communication mediated by highly conserved functional residues and potential allosteric regulation of PTEN. We identified a salient structural-communication pathway that extends across the inter-domain interface for cancer-only mutations. In contrast, the structural-communication pathway is predominantly restricted to the phosphatase domain for ASD-only mutations. Our integrative approach supports the prediction and potential modulation of the relevant conformational states that influence structural communication and long-range perturbations associated with mutational effects that lead to PTEN-ASD or PTEN-cancer phenotypes.

Keywords: PTEN; PTEN allostery; PTEN interactome; conformation dynamics; germline PTEN mutations; molecular dynamics simulation; network proximity analysis.

Figure 1

Significant Network Proximity of PTEN Influencers to Known ASD- or Cancer-Associated Genes within the Human Protein-Protein Interactome Network Model (A) Connectivity distribution of the human interactome that was used in this study. (B) A significant network proximity of PTEN influencers with known ASD-associated genes within the human interactome. (C and D) Significant network proximities of PTEN influencers with known somatic mutant genes (C) or with known breast cancer germline mutant genes (D) within the human interactome. The network proximity analyses of PTEN influencers with more than 10 different other cancer types are provided in Table S1.

Figure 2

Degree Density Distribution of Core and Surface Residues in ASD- and Cancer-Associated Mutations Density distribution on core and surface residues for (A) WT PTEN, (B) three-dimensional PTEN structure, (C) ASD only, (D) cancer only, (E) mutations shared across both phenotypes, and (F) one mutation with co-existing ASD and cancer. Core residues encompass two key regions: (1) the active site (residues 32–35; residues overlapping P loop, ATP B-binding motif, and pα4 loop, residues 122–138) and (2) inter-domain (motif 1, residues 169–180; motif 2, residues 250–259, and motif 3, residues 264–276). The core (blue) and surface (red) residues are mapped within the three-dimensional structure of PTEN (inset).

Figure 3

Residue-based Betweenness Centrality Estimation Plot Profiles for ASD- and Cancer-Associated PTEN Germline Mutations Dynamics-based analysis of betweenness network centrality for (A) ASD only, (B) cancer only, and (C) mutations shared across both phenotypes. The gray-filled curve indicates the complete Δ distribution given the observed data. In-line with the median of each group, the Δ is indicated by the black circle. The 95% confidence interval of Δ is illustrated by the vertical black line. Significant betweenness centrality peaks were mapped to the three-dimensional PTEN structure for each phenotype (insets).

Figure 4

Residue Interaction Connectivity in Catalytic Loops of ASD- and Cancer-Associated Mutations Connectivity in (A) the P loop (residues 123–131), (B) the WPD loop (residues 88–98), and (C) the TI loop (residues 160–171). The size and color of the nodes within the residue-interaction network indicate the importance of the hub node in the network, revealing it as a key player in structural communication (e.g., expansion in size and progression toward red color indicate increasing connectivity).

Figure 5

Global Metapath of Communication in ASD- and Cancer-Associated Mutations The figure shows (A) ASD only, (B) cancer only, (C) mutations shared across both phenotypes, and (D) one mutation resulting in co-existing ASD and cancer. The metapath outlines critical nodes where the spheres (cyan) are centered on C-alpha atoms and the diameter is proportional to the number of edges made by the node.