Cargando…

Shape shifting: The multiple conformational substates of the PTEN N‐terminal PIP(2) ‐binding domain

The Phosphatase and TENsin homolog deleted on chromosome 10 (PTEN) is a chief regulator of a variety of cellular processes including cell proliferation, migration, growth, and death. It is also a major tumor suppressor gene that is frequently mutated or lost under cancerous conditions. PTEN encodes...

Descripción completa

Detalles Bibliográficos
Autores principales: Dawson, Jennifer E., Smith, Iris Nira, Martin, William, Khan, Krishnendu, Cheng, Feixiong, Eng, Charis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9004235/
https://www.ncbi.nlm.nih.gov/pubmed/35481646
http://dx.doi.org/10.1002/pro.4308
Descripción
Sumario:The Phosphatase and TENsin homolog deleted on chromosome 10 (PTEN) is a chief regulator of a variety of cellular processes including cell proliferation, migration, growth, and death. It is also a major tumor suppressor gene that is frequently mutated or lost under cancerous conditions. PTEN encodes a dual‐specificity (lipid and protein) phosphatase that negatively regulates the PI3K/AKT/mTOR signaling pathway where the PIP(2)‐binding domain (PBD) regulates the lipid phosphatase function. Unfortunately, despite two decades of research, a full‐length structure of PTEN remains elusive, leaving open questions regarding PTEN's disordered regions that mediate protein stability, post‐translational modifications, protein–protein interactions, while also hindering the design of small molecules that can regulate PTEN's function. Here, we utilized a combination of crosslinking mass spectrometry, in silico predicted structural modeling (including AlphaFold2), molecular docking, molecular dynamics simulations, and residue interaction network modeling to obtain structural details and molecular insight into the behavior of the PBD of PTEN. Our study shows that the PBD exists in multiple conformations which suggests its ability to regulate PTEN's variety of functions. Studying how these specific conformational substates contribute to PTEN function is imperative to defining its function in disease pathogenesis, and to delineate ways to modulate its tumor suppressor activity.