{"i":"PTEN","#text":"Comparative Protein Structural Network Analysis Reveals C-Terminal Tail Phosphorylation Structural Communication Fingerprint in-Associated Mutations in Autism and Cancer."}

Scientists studied how mutations in the PTEN gene affect protein structure differently in autism compared to cancer. PTEN mutations can cause both cancer and autism in the same genetic condition called PTEN hamartoma tumor syndrome. The study found that autism-related mutations change the protein structure differently than cancer-related mutations, suggesting they work through different mechanisms. This could lead to new treatment approaches tailored to specific types of PTEN mutations.

This computational study used protein structural network analysis to investigate how PTEN gene mutations affect protein structure differently in autism versus cancer. PTEN is a critical gene that regulates cell growth and division, and mutations in PTEN cause PTEN hamartoma tumor syndrome (PHTS), which is associated with both cancer risk and autism spectrum disorder. The researchers found that PTEN mutations linked to autism create different structural changes in the protein compared to cancer-associated mutations, particularly affecting how the protein's tail region communicates with other parts. These findings suggest that autism-associated and cancer-associated PTEN mutations may work through different mechanisms, potentially opening new avenues for targeted treatments.

This research provides theoretical foundation for understanding why PTEN mutations cause both autism and cancer, potentially leading to mutation-specific treatments. However, findings require extensive validation through laboratory studies and clinical trials before practical application.

This is a computational modeling study without experimental validation. No sample size or clinical data reported. Findings are theoretical and require laboratory and clinical validation before clinical application.

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. Germlinemutations predispose individuals tohamartoma 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 ofvariants reveal potential allosteric druggable target sites as a viable and currently unexplored treatment approach for individuals with different PHTS-associated mutations.