The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane

Jang, Hyunbum; Smith, Iris Nira; Eng, Charis; Nussinov, Ruth

doi:10.1016/j.isci.2021.102438

Cited by 42 publications

(61 citation statements)

References 71 publications

(126 reference statements)

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“…In brief, full-length wildtype (WT) human PTEN (residues 1-403) was expressed with a C-terminal 6-His tag (a gift from Alonzo Ross [addgene plasmid #20741]) 57 and purified using a modified protocol (Redfern et al, 57 Johnston and Raines 58 ). The full-length PTEN models were predicted using AlphaFold2, 24,26 RoseTTAFold, 27 and I-TASSER (as previously described 21 ). PBD orientation reproducibility and model quality assessment (pLDDT 59,60 ) are shown in Figure S1 and Table S1.…”

Section: Methodsmentioning

confidence: 99%

“…HADDOCK treats PBD as separate from the rest of PTEN, so an unambiguous distance restraint was added between the "cut" ends. When it is modeled as an α-helix with a flexible linker (residues [11][12][13][14][15][16][17][18][19][20][21][22], the AlphaFold2 and mid sites are favored (Figure S4f and Table S4 test 5). PBD at the mid site satisfies more of the crosslinks than when it was at the AlphaFold2 site (Table S5), which suggests the mid site as a possible PBD binding orientation.…”

Section: Multiple Pbd Binding Orientations Observed During Haddock Do...mentioning

confidence: 99%

“…Impressive improvements have been made recently in protein structure prediction. In previous work, we constructed a full-length model of PTEN 21 using I-TASSER. 22,23 Now, taking advantage of next-generation Deep Machine Learning methods, we have constructed full-length models of PTEN using AlphaFold2 [24][25][26] and RoseTTAFold.…”

Section: Multiple Observed and Predicted Pbd Intermolecular Binding S...mentioning

confidence: 99%

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Shape shifting: The multiple conformational substates of the PTEN N‐terminal PIP₂‐binding domain

et al. 2022

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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 PIP2‐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.

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Section: Methodsmentioning

confidence: 99%

Section: Multiple Pbd Binding Orientations Observed During Haddock Do...mentioning

confidence: 99%

Section: Multiple Observed and Predicted Pbd Intermolecular Binding S...mentioning

confidence: 99%

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Shape shifting: The multiple conformational substates of the PTEN N‐terminal PIP₂‐binding domain

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“…The mutations should be sufficiently strong to obtain a high population of the activated proteins. Mutation strength relates to its mechanism of protein activation ( 72 – 75 ). In cancer, hyperactivation leads to cell proliferation; extremely vigorous activation signal can lead to oncogene-induced senescence (OIS).…”

Section: Cancer Evolution and Neurodevelopmental Pathologiesmentioning

confidence: 99%

“…GAP-induced hydrolysis is impaired by Gly12 but not by A146T mutations, which act by accelerating nucleotide exchange. On the other hand, mutations in tumor suppressor PTEN abolish its activation mechanism at the membrane ( 75 ).…”

Section: The Mechanism Of Activation and Signaling Strengthmentioning

confidence: 99%

How can same-gene mutations promote both cancer and developmental disorders?

2022

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Control of phosphatidylinositol‐3‐kinase signaling by nanoscale membrane compartmentalization

Cabral-Dias

Antonescu

2022

BioEssays

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Phosphatidylinositol‐3‐kinases (PI3Ks) are lipid kinases that produce 3‐phosphorylated derivatives of phosphatidylinositol upon activation by various cues. These 3‐phosphorylated lipids bind to various protein effectors to control many cellular functions. Lipid phosphatases such as phosphatase and tensin homolog (PTEN) terminate PI3K‐derived signals and are critical to ensure appropriate signaling outcomes. Many lines of evidence indicate that PI3Ks and PTEN, as well as some specific lipid effectors are highly compartmentalized, either in plasma membrane nanodomains or in endosomal compartments. We examine the evidence for specific recruitment of PI3Ks, PTEN, and other related enzymes to membrane nanodomains and endocytic compartments. We then examine the hypothesis that scaffolding of the sources (PI3Ks), terminators (PTEN), and effectors of these lipid signals with a common plasma membrane nanodomain may achieve highly localized lipid signaling and ensure selective activation of specific effectors. This highlights the importance of spatial regulation of PI3K signaling in various physiological and disease contexts.

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The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane

Cited by 42 publications

References 71 publications

Shape shifting: The multiple conformational substates of the PTEN N‐terminal PIP₂‐binding domain

Shape shifting: The multiple conformational substates of the PTEN N‐terminal PIP₂‐binding domain

How can same-gene mutations promote both cancer and developmental disorders?

Control of phosphatidylinositol‐3‐kinase signaling by nanoscale membrane compartmentalization

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The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane

Cited by 42 publications

References 71 publications

Shape shifting: The multiple conformational substates of the PTEN N‐terminal PIP2‐binding domain

Shape shifting: The multiple conformational substates of the PTEN N‐terminal PIP2‐binding domain

How can same-gene mutations promote both cancer and developmental disorders?

Control of phosphatidylinositol‐3‐kinase signaling by nanoscale membrane compartmentalization

Contact Info

Product

Resources

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Shape shifting: The multiple conformational substates of the PTEN N‐terminal PIP₂‐binding domain

Shape shifting: The multiple conformational substates of the PTEN N‐terminal PIP₂‐binding domain