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Elucidating PTEN Conformational Dynamics and Phosphatase Regulation via Integrative Modeling and Mutation Prediction

ABSTRACT: PTEN (Phosphatase and TENsin homolog deleted on chromosome ten) is a major tumor suppressor gene that is frequently mutated or lost under cancerous conditions. PTEN is a dual-specificity phosphatase that negatively regulates the PI3K/AKT/mTOR signaling pathway at the plasma membrane (PM). Its functional regulation and cellular localization are known to be conformationally driven. Access to the PM is phospho-regulated by open and closed PTEN forms. However, clarifying the underlying structural mechanisms is still an open avenue of research. Here, we apply an integrative structural modeling approach, combining coarse-grained and all-atom molecular dynamics with experimental crosslinking mass spectrometry. Conformational exchange between an “eased” form and a “strained” form brings the protein’s phosphatase and C2 domains closer together, blocking the catalytic site, and affecting the loops involved in PM binding. Our full-length PTEN models, AlphaMissense, and RaSP were used to better predict the consequences of PTEN mutations.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Pten Hamartoma Tumor Syndrome

SUBMITTER: Belinda Willard

LAB HEAD: Jennifer Erin Dawson

PROVIDER: PXD059974 | Pride | 2025-06-09

REPOSITORIES: Pride

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			Action	DRS
	Eng_PTEN.fasta	Fasta
	WT_DHSO_25mM_Dimer_DDA_1.msf	Msf
	WT_DHSO_25mM_Dimer_DDA_1.mzML	Mzml
	WT_DHSO_25mM_Dimer_DDA_1.mzid.gz	Mzid
	WT_DHSO_25mM_Dimer_DDA_1.raw	Raw

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