Database Accession: DI1000328
Name: PI3K p85 N-terminal SH2 domain complexed with a CD28-derived phosphotyrosine-containing peptide
PDB ID: 5gji
Experimental method: X-ray (0.90 Å)
Source organism: Homo sapiens
Proof of disorder:
Primary publication of the structure:
Inaba S, Numoto N, Ogawa S, Morii H, Ikura T, Abe R, Ito N, Oda M
Crystal Structures and Thermodynamic Analysis Reveal Distinct Mechanisms of CD28 Phosphopeptide Binding to the Src Homology 2 (SH2) Domains of Three Adaptor Proteins.
(2017) J. Biol. Chem. 292: 1052-1060
PMID: 27927989
Abstract:
Full activation of T cells and differentiation into effector T cells are essential for many immune responses and require co-stimulatory signaling via the CD28 receptor. Extracellular ligand binding to CD28 recruits protein-tyrosine kinases to its cytoplasmic tail, which contains a YMNM motif. Following phosphorylation of the tyrosine, the proteins growth factor receptor-bound protein 2 (Grb2), Grb2-related adaptor downstream of Shc (Gads), and p85 subunit of phosphoinositide 3-kinase may bind to pYMNM (where pY is phosphotyrosine) via their Src homology 2 (SH2) domains, leading to downstream signaling to distinct immune pathways. These three adaptor proteins bind to the same site on CD28 with variable affinity, and all are important for CD28-mediated co-stimulatory function. However, the mechanism of how these proteins recognize and compete for CD28 is unclear. To visualize their interactions with CD28, we have determined the crystal structures of Gads SH2 and two p85 SH2 domains in complex with a CD28-derived phosphopeptide. The high resolution structures obtained revealed that, whereas the CD28 phosphopeptide bound to Gads SH2 is in a bent conformation similar to that when bound to Grb2 SH2, it adopts a more extended conformation when bound to the N- and C-terminal SH2 domains of p85. These differences observed in the peptide-protein interactions correlated well with the affinity and other thermodynamic parameters for each interaction determined by isothermal titration calorimetry. The detailed insight into these interactions reported here may inform the development of compounds that specifically inhibit the association of CD28 with these adaptor proteins to suppress excessive T cell responses, such as in allergies and autoimmune diseases.
Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown. Molecular function:
phosphatidylinositol-4,5-bisphosphate 3-kinase activity Catalysis of the reaction: 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + ATP = a 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + ADP + 2 H(+).
protein kinase binding Interacting selectively and non-covalently with a protein kinase, any enzyme that catalyzes the transfer of a phosphate group, usually from ATP, to a protein substrate.
Biological process:
regulation of phosphatidylinositol 3-kinase signaling Any process that modulates the frequency, rate or extent of signal transduction mediated by the phosphatidylinositol 3-kinase cascade.
T cell costimulation The process of providing, via surface-bound receptor-ligand pairs, a second, antigen-independent, signal in addition to that provided by the T cell receptor to augment T cell activation.
interleukin-7-mediated signaling pathway A series of molecular signals initiated by the binding of interleukin-7 to a receptor on the surface of a cell, and ending with regulation of a downstream cellular process, e.g. transcription.
positive regulation of transcription from RNA polymerase II promoter Any process that activates or increases the frequency, rate or extent of transcription from an RNA polymerase II promoter.
phosphatidylinositol phosphorylation The process of introducing one or more phosphate groups into a phosphatidylinositol, any glycerophosphoinositol having one phosphatidyl group esterified to one of the hydroxy groups of inositol.
phosphatidylinositol-mediated signaling A series of molecular signals in which a cell uses a phosphatidylinositol-mediated signaling to convert a signal into a response. Phosphatidylinositols include phosphatidylinositol (PtdIns) and its phosphorylated derivatives.
T cell receptor signaling pathway A series of molecular signals initiated by the cross-linking of an antigen receptor on a T cell.
protein metabolic process The chemical reactions and pathways involving a specific protein, rather than of proteins in general. Includes protein modification.
organic substance biosynthetic process The chemical reactions and pathways resulting in the formation of an organic substance, any molecular entity containing carbon.
negative regulation of biological process Any process that stops, prevents, or reduces the frequency, rate or extent of a biological process. Biological processes are regulated by many means; examples include the control of gene expression, protein modification or interaction with a protein or substrate molecule.
apoptotic signaling pathway A series of molecular signals which triggers the apoptotic death of a cell. The pathway starts with reception of a signal, and ends when the execution phase of apoptosis is triggered.
cell activation A change in the morphology or behavior of a cell resulting from exposure to an activating factor such as a cellular or soluble ligand.
positive regulation of cytokine production Any process that activates or increases the frequency, rate or extent of production of a cytokine.
regulation of organelle organization Any process that modulates the frequency, rate or extent of a process involved in the formation, arrangement of constituent parts, or disassembly of an organelle.
positive regulation of cellular component organization Any process that activates or increases the frequency, rate or extent of a process involved in the formation, arrangement of constituent parts, or disassembly of cell structures, including the plasma membrane and any external encapsulating structures such as the cell wall and cell envelope.
positive regulation of signal transduction Any process that activates or increases the frequency, rate or extent of signal transduction.
Cellular component:
Structural annotations of the participating protein chains.Entry contents: 2 distinct polypeptide molecules
Chains: B, A
Notes: No modifications of the original PDB file.
Name: T-cell-specific surface glycoprotein CD28
Source organism: Homo sapiens
Length: 8 residues
Sequence:Sequence according to PDB SEQRESSDYMNMTP
The sequence contains the following modified/non-standard residues:
• phosphotyrosine (Y) at position 191 (PDB position: 191)
UniProtKB AC: P10747 (positions: 189-196) Coverage: 3.6%
UniRef90 AC: UniRef90_P10747 (positions: 189-196)
Name: Phosphatidylinositol 3-kinase regulatory subunit alpha
Source organism: Homo sapiens
Length: 108 residues
Sequence:Sequence according to PDB SEQRESGSNMSLQNAEWYWGDISREEVNEKLRDTADGTFLVRDASTKMHGDYTLTLRKGGNNKLIKIFHRDGKYGFSDPLTFSSVVELINHYRNESLAQYNPKLDVKLLYPVSK
UniProtKB AC: P27986 (positions: 323-430) Coverage: 14.9%
UniRef90 AC: UniRef90_P27986 (positions: 324-430)
Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding. Chain B:
The protein region involved in the interaction contains a known functional linear motif (LIG_SH2_GRB2).
Chain A:
The SH2 domain involved in the interaction is known to adopt a stable structure in isolation (see Pfam domain PF00017). A solved monomeric structure of the domain is represented by PDB ID 1fhs.
Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap). No related structure was found in the Protein Data Bank.
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