![]() Microclusters are membrane-associated aggregations (up to 500 nm in diameter) of signaling proteins formed immediately after stimulation of the TCR. On a supramolecular scale, scaffold and adaptor proteins are necessary for the oligomerization of signaling complexes and the formation of microclusters during and prior to the assembly of the immune synapse. PLCg1 primarily uses pY132 on LAT for its association, but it is not stably recruited when interactions of GADS or GRB2 with LAT are obstructed. This can be explained by statistical rebinding or by the fact that interactions with LAT are interdependent and mutually stabilize each other. The adaptor proteins GADS and GRB2 have single SH2 domains nevertheless, both require at least two phosphorylated tyrosines for their association with LAT. The proline-rich region of SLP76 also acts as a binding site for PLCg1. Both proteins are required for normal T cell development. GRB2-related adaptor downstream of SHC (GADS) forms an ever-present complex with the adaptor SH2-domain-containing leukocyte protein of 76 kDa (SLP76), by interaction of its Cterminal SH3 domain with the RSTK motif within the prolinerich region of SLP76. Together these proteins form an interconnected molecular framework that forms the basis of the main stimulatory signaling network in T cells. These phosphotyrosines form binding sites for the SRC homology 2 (SH2) domains of an array of signaling proteins, among which are phospholipase C g1 (PLCg1), growth factor receptor-bound protein 2 (GRB2) and the GADS-SLP76 complex. Introduction lated by ZAP70 (z-chain-associated protein kinase, 70 kDa), leukocyte C-terminal SRC kinase (LCK), spleen tyrosine kinase (SYK), and IL2-inducible T cell kinase (ITK). Here, we explored the minimal structural requirement for a scaffold protein by coupling multiple copies of a prolinerich peptide corresponding to an interaction motif for the SH3 Such microclusters are prominent in early T cell signaling. Furthermore, multivalent interactions between the scaffold and other signaling proteins contribute to the formation of protein microclusters. In cellular signal transduction, scaffold proteins provide binding sites to organize signaling proteins into supramolecular complexes and act as nodes in the signaling network. Furthermore, following import into Jurkat T cell leukemia cells, this synthetic scaffold enhanced the formation of microclusters of signaling proteins. This can be explained by the cross-linking of GADS into larger complexes. When added to GADScontaining cell lysates, these scaffolds (but not individual peptides) promoted the binding of GADS to peptide microarrays. Adjobo-Hermans, and Roland Brock* domain of the adaptor protein GADS to an N-(2-hydroxypropyl)methacrylamide polymer backbone. A Peptide-Functionalized Polymer as a Minimal Scaffold Protein To Enhance Cluster Formation in Early T Cell Signal Transduction J. ![]()
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