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Phosphorylation States of PEA‐15 Control Binding Specificity and Regulate Cell Proliferation and Apoptosis
Author(s) -
Crespo Sergio,
Hassan Sherouk,
Cabezas Andres,
Wei Yufeng
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.631.12
Subject(s) - fadd , phosphorylation , serine , microbiology and biotechnology , phosphoprotein , programmed cell death , biology , apoptosis , cell growth , signal transduction , death domain , biochemistry , caspase
Phosphoprotein enriched in astrocytes, 15 KDa (PEA‐15), is a small, cytoplasmic, death‐effector domain (DED) containing protein, found pervasively in mammals. It is ubiquitously expressed in different tissues, and has been known to be involved in several cellular pathways, including apoptosis and cell proliferation. This protein appeals to us and many other scientists because it is present in the cells in two different forms, phosphorylated PEA‐15 (at serine 104 and serine 116) and unphosphorylated PEA‐15, each interacting with different proteins at distinct biological pathways. PEA‐15 in its unphosphorylated state, interacts with ERK1/2 and prevents cell proliferation, while phosphorylated form interacts with Fas‐Associated Death Domain (FADD) protein and inhibits death receptor‐initiated apoptosis. Our initial NMR spectroscopic study showed that PEA‐15 undergoes conformational changes when it becomes phosphorylated at both serine residues, mimicked by serine to aspartic acid mutations (PEA‐15DD). The modulation of conformation switches the binding specificity of PEA‐15 from ERK1/2 to FADD, and changes its function from promoting cell death to cell survival. Based on our most recent results, we hypothesize that the DED conformation is allosterically controlled by the phosphorylation states of the C‐terminal tail, which in turn determines the binding specificity of the protein. Our ongoing research aims to broaden our understanding of the FADD/PEA‐15DD complex in vivo using NMR. In our phosphostasis model, we speculate that the balance between phosphorylated and unphosphorylated PEA‐15 is strictly regulated in different cell types and tissues to maintain the optimal cellular condition, and disruptions of the delicate balance could be detrimental to the cells, resulting in unregulated proliferation or elevated cell death. Support or Funding Information U.S. Education Department Minority Science & Engineering Improvement Program Grant # P120A160084 NIH AREA Grant #CA179410 USED Title III Part F, HSI‐STEM & Articulation Grant #P03C160155 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .