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Nature Structural & Molecular Biology

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Dynamic regulation of CD28 conformation and signaling by charged lipids and ions

Wei Yang1,2,7 , Weiling Pan1,7, Shuokai Chen1,7, Nicola Trendel3,7 , Shutan Jiang1,7, Feng Xiao4, Manman Xue1,Wei Wu1, Zeli Peng1, Xiaoxi Li5 , Hongbin Ji5 , Xiaolong Liu5, Hai Jiang5, Haopeng Wang6, Hongbin Shen4,Omer Dushek3 , Hua Li1 & Chenqi Xu1,6

Nature Structural & Molecular Biology

This paper is about the regulation of CD28 confirmation and signaling. As all we know, CD3-CD28 signaling pathway play an important role in T cell activation. T cell activation requires two signals: a major antigen-induced signal from the TCR, and a secondary signal from costimulatory receptors. The most studied costimulatory receptor is CD28, which has a crucial function in T cell activation. Several key aspects of CD28 signaling remain obscure. In this study, we found that CD28 activity is regulated by negatively charged acidic phospholipids and positively charged Ca2+ ions. To explore whether ionic protein-lipid regulation occurs in a more general manner, the author carried out a systematic bioinformatics analysis to calculate the isoelectric point (pI) value of the first ten-residue stretch in the cytoplasmic domain of single-pass plasma membrane proteins. They confirmed that CD28 contains?conserved juxtamembrane polybasic regions. They used solution NMR spectroscopy to study CD28CD-lipid interaction at atomic resolution and found that the CD28 cytoplasmic domain inserts into the membrane bilayer. Then they determined the structure of membrane-bound CD28 in the context of a lipid bilayer with Xplor-NIH and confirmed that lipid-bound CD28CD remained dynamic even when fully embedded in the membrane bilayer. To further study the role of CD28CD membrane association, they designed a CD28 mutant with impaired membrane-binding capability and performed the Ca2+ imaging. Results shown that TCR signaling induces local Ca2+ ion enrichment around CD28 and microdialysis assay confirmed that an increase in Ca2+ concentration substantially reduced the binding of CD28CD to acidic phospholipids and Ca2+ opened the CD28 cytoplasmic domain to facilitate?signaling. Furthermore, they construct a mathematical model of immune receptor conformational dynamics and showed the importance of Ca2+ feedback to the antigen sensitivity of T cells.

This paper report a new mechanism for the regulation of CD28 signaling that involves dynamic interplay between acidic phospholipids and Ca2+ to set the local electrostatic environment. This paper gives a deep insight into this research area and introduces a new methods for membrane protein research.


A Chemical-Genetic Approach Reveals the Distinct Roles of GSK3a and GSK3b in Regulating Embryonic Stem Cell Fate

Xi Chen,1 Ruizhe Wang,1 Xu Liu,2 Yongming Wu,1 Tao Zhou,1 Yujia Yang,1 Andrew Perez,1 Ying-Chu Chen,2 Liang Hu,1Jean Paul Chadarevian,1 Amir Assadieskandar,2 Chao Zhang,2,* and Qi-Long Ying1,3,*

Development cell

Glycogen synthase kinase 3 (GSK3), a serine/threonine protein kinase, plays a central role in multiple intracellular signaling pathways, including those activated by Wnt/b-catenin, sonic hedgehog, Notch, growth factors/receptor tyrosine kinases, and G-protein-coupled receptors. In mammals, GSK3 is encoded by two paralogous genes, Gsk3a and Gsk3b, which are 90% identical with respect to the amino acid sequences within their kinase domains. Previous studies have suggested that GSK3a and GSK3b had overlapping functions in regulating the Wnt/b-catenin signaling pathway. On the other hand, knockout of GSK3a or GSK3b in mice produced distinct phenotypes.While GSK3b knockout resulted in embryonic lethality, GSK3a knockout mice were viable and had only minor defects in hepatic glycogen metabolism. These two GSK3 isozymes have non-redundant roles during development, the basis of which is not clear. In this paper the author used a chemical-genetic approach that involves genetic modification in the protein of interest and the use of inhibitor analogs that specifically recognize the modified protein to efficiently distinguish between highly homologous proteins to identify the function of individual GSK3 isozymes. To define the roles of individual GSK3 isozymes, they first generated Gsk3a?/?, Gsk3b?/?, and Gsk3a/b double-knockout (DKO) E14TG2a mouse ESC lines via CRISPR/Cas9-mediated gene argeting and showed that either GSK3 isozyme can inhibit canonical Wnt/b-catenin signaling when the other is ablated. Further study showed that deletion of Either Gsk3a or Gsk3b is not sufficient to mimic the effect of CHIR in promoting ESC self-renewal. Because no existing small molecules can distinguish with high selectivity between GSK3a and GSK3b, they employed a chemical-genetic approach to achieve specific inhibition of individual GSK3 isozymes. Using this cell model, they confirmed that GSK3a and GSK3b play distinct and nonredundant roles in regulating cell fates when both kinases are present in ESCs. Further study confirmed that GSK3b has a stronger affinity than GSK3a to interact with and phosphorylate b-Catenin. RNA-seq results further demonstrated that GSK3a and GSK3b play distinct roles in regulating neural differentiation of ESCs.

This paper opens new avenues for defining GSK3 isozyme-specific functions in various cellular processes.


Edited by Biaolong Deng