Abstract 3845: Structural mechanisms of how PTEN mutations degrade function at the membrane and life expectancy of carriers of mutations in the human brain
Authors: Jang Hyunbum , Chen Jiaye , Iakoucheva Lilia M. , Nussinov Ruth 
Published: April 2023

PTEN negatively regulates PI3K/AKT/mTOR signaling through dephosphorylation of PIP3 to PIP2. PTEN dysfunction triggers disease phenotypes, ranging from cancer and PHTS to NDDs such as ASD. The most common PTEN mutations, nonsense, frameshift, and deletion/insertion, may cause premature termination of translation. PTEN has a considerable number of missense mutations that may result in loss of protein function through reduced catalytic activity and protein stability. To decipher mechanistic details of the mutations and structural features of the mutant proteins, comprehensive computational studies were performed for PTEN mutants at an anionic lipid bilayer containing PC, PS, PIP2, and PIP3. Six PTP mutations (Y68H, H93R, A126T, R130Q, G132D, R173C) and two C2 mutations (F241S, D252G) were considered. The PTP mutations are known to associate with cancer, PHTS, macrocephaly, and ASD, while the C2 mutations are exclusively related to macrocephaly and ASD. Our studies indicate that the PTEN mutants can effectively absorb the anionic lipid bilayer, similar to wild-type PTEN. However, Y68H significantly disrupts the core of PTP domain, reducing protein stability. H93R hijacks the substate PIP3, interrupting the catalytic site residues recruitment of the substate for catalysis. A126T, R130Q, and G132D in the P loop directly influence the dynamics of the loop, yielding a collapsed loop conformation. The collapsed P loop loses the interaction with the WPD loop, leading to dehydration in the catalytic site. R173C and D252G at the interface between two major domains disrupt the domain-domain interaction, allosterically biasing the P loop dynamics. However, F241S in C2 exhibits less effective allosteric connection to the catalytic site than that observed in the wild type. PCA of the sampled conformations found that the macrocephaly and ASD-related H93R and F241S are likely to sample the conformations present in the wild type. In contrast, the sampled conformations for the cancer and PHTS-related Y68H, A126T, and G132D are different from those for the wild type. These distinct structural features seem to correlate with mutation strength and timing of the expression of the genes that determine the cancer and NDD outcomes. The isoform expression data extracted from the BrainSpan indicate that exon 5 is impacted by NDD or non-NDD mutations. Interestingly, PTEN splicing isoforms that do not carry exon 5 are exclusively impacted by the NDD mutations, F241S and D252G. The increased life expectancy of PTEN variants carriers carrying exons 5 and 7 is highly correlated to increased lifetime risk for certain cancers. Our results underscore the detailed structural and functional mechanisms of PTEN with mutations at the membrane, and suggest that tissue-specific splicing isoform expression should be taken into consideration while predicting the effect of mutations in various diseases.

Citation Format: Hyunbum Jang, Jiaye Chen, Lilia M. Iakoucheva, Ruth Nussinov. Structural mechanisms of how PTEN mutations degrade function at the membrane and life expectancy of carriers of mutations in the human brain. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3845.