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

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

doi:10.1016/j.isci.2021.102438

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

iScience. 2021 Apr 17;24(5):102438. doi: 10.1016/j.isci.2021.102438. eCollection 2021 May 21.

Authors

Hyunbum Jang¹, Iris Nira Smith², Charis Eng^{2

3

4

5}, Ruth Nussinov^{1

6}

Affiliations

¹ Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, MD 21702, USA.
² Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
³ Center for Personalized Genetic Healthcare, Cleveland Clinic Community Care and Population Health, Cleveland, OH 44195, USA.
⁴ Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
⁵ Germline High Risk Cancer Focus Group, Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
⁶ Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.

Abstract

Tumor suppressor PTEN, the second most highly mutated protein in cancer, dephosphorylates signaling lipid PIP₃ produced by PI3Ks. Excess PIP₃ promotes cell proliferation. The mechanism at the membrane of this pivotal phosphatase is unknown hindering drug discovery. Exploiting explicit solvent simulations, we tracked full-length PTEN trafficking from the cytosol to the membrane. We observed its interaction with membranes composed of zwitterionic phosphatidylcholine, anionic phosphatidylserine, and phosphoinositides, including signaling lipids PIP₂ and PIP₃. We tracked its moving away from the zwitterionic and getting absorbed onto anionic membrane that harbors PIP₃. We followed it localizing on microdomains enriched in signaling lipids, as PI3K does, and observed PIP₃ allosterically unfolding the N-terminal PIP₂ binding domain, positioning it favorably for the polybasic motif interaction with PIP₂. Finally, we determined PTEN catalytic action at the membrane, all in line with experimental observations, deciphering the mechanisms of how PTEN anchors to the membrane and restrains cancer.

Keywords: Cancer; In Silico Biology; Structural Biology.

Grants and funding

K99 GM143552/GM/NIGMS NIH HHS/United States