Comparative Protein Structural Network Analysis Reveals C-Terminal Tail Phosphorylation Structural Communication Fingerprint in PTEN-Associated Mutations in Autism and Cancer

Abstract

PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a tightly regulated dual-specificity phosphatase and key regulator of the PI3K/AKT/mTOR signaling pathway. PTEN phosphorylation at its carboxy-terminal tail (CTT) serine/threonine cluster negatively regulates its tumor suppressor function by inducing a stable, closed, and inactive conformation. Germline PTEN mutations predispose individuals to PTEN hamartoma tumor syndrome (PHTS), a rare inherited cancer syndrome and, intriguingly, one of the most common causes of autism spectrum disorder (ASD). However, the mechanistic details that govern phosphorylated CTT catalytic conformational dynamics in the context of PHTS-associated mutations are unknown. Here, we utilized a comparative protein structure network (PSN)-based approach to investigate PTEN CTT phosphorylation-induced conformational dynamics specific to PTEN-ASD compared to PTEN-cancer phenotypes. Results from our study show differences in structural flexibility, inter-residue contacts, and allosteric communication patterns mediated by CTT phosphorylation, differentiating PTEN-ASD and PTEN-cancer phenotypes. Further, we identified perturbations among global metapaths and community network connections within the active site and inter-domain regions, indicating the significance of these regions in transmitting information across the PSN. Together, our studies provide a mechanistic underpinning of allosteric regulation through the coupled interplay of CTT phosphorylation conformational dynamics in PTEN-ASD and PTEN-cancer mutations. Importantly, the detailed atomistic interactions and structural consequences of PTEN variants reveal potential allosteric druggable target sites as a viable and currently unexplored treatment approach for individuals with different PHTS-associated mutations.

The Role of C2 Domains in Two Different Phosphatases: PTEN and SHIP2

“…However, the results also raise the following question: What is the role of the C2 domain in SHIP2? Interestingly, phosphorylation of the C-terminus of PTEN (i.e., the "C2-end") has previously been shown to allosterically affect PTEN phenotypes [36], suggesting that C2 acts both as a lipid anchor and as an allosteric regulator in PTEN. So, C2 may also act as an allosteric modulator in SHIP2.…”

The Role of C2 Domains in Two Different Phosphatases: PTEN and SHIP2

“…Interestingly, phosphorylation of the C-terminus of PTEN (i.e. the "C2-end") have previously been shown to allosterically affect PTEN phenotypes [35], suggesting that C2 also acts as an allosteric regulator in PTEN, so C2 play several roles in PTEN.…”