7JTX

the structural basis of PTEN regulation by multi-site phosphorylation

Summary for 7JTX

• Entry DOI: 10.2210/pdb7jtx/pdb
• Descriptor: Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (1 entity in total)
• Functional Keywords: pten, phosphatase, cellular localization, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 42338.83

Authors

Park, E.,Dempsey, D.R.,Cole, P. (deposition date: 2020-08-18, release date: 2021-09-01, Last modification date: 2023-10-18)

Primary citation

Dempsey, D.R.,Viennet, T.,Iwase, R.,Park, E.,Henriquez, S.,Chen, Z.,Jeliazkov, J.R.,Palanski, B.A.,Phan, K.L.,Coote, P.,Gray, J.J.,Eck, M.J.,Gabelli, S.B.,Arthanari, H.,Cole, P.A.
The structural basis of PTEN regulation by multi-site phosphorylation.
Nat.Struct.Mol.Biol., 28:858-868, 2021

PubMed Abstract: Phosphatase and tensin homolog (PTEN) is a phosphatidylinositol-3,4,5-triphosphate (PIP) phospholipid phosphatase that is commonly mutated or silenced in cancer. PTEN's catalytic activity, cellular membrane localization and stability are orchestrated by a cluster of C-terminal phosphorylation (phospho-C-tail) events on Ser380, Thr382, Thr383 and Ser385, but the molecular details of this multi-faceted regulation have remained uncertain. Here we use a combination of protein semisynthesis, biochemical analysis, NMR, X-ray crystallography and computational simulations on human PTEN and its sea squirt homolog, VSP, to obtain a detailed picture of how the phospho-C-tail forms a belt around the C2 and phosphatase domains of PTEN. We also visualize a previously proposed dynamic N-terminal α-helix and show that it is key for PTEN catalysis but disordered upon phospho-C-tail interaction. This structural model provides a comprehensive framework for how C-tail phosphorylation can impact PTEN's cellular functions.

PubMed: 34625746
DOI: 10.1038/s41594-021-00668-5

Experimental method

X-RAY DIFFRACTION (3.23 Å)