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.
from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2jf85iL
via IFTTT
Εγγραφή σε:
Σχόλια ανάρτησης (Atom)
Δημοφιλείς αναρτήσεις
-
Introduction. Congenital Palmaris Longus (PL) absence was found in 15%–20.25% of population globally. This condition and Flexor Digitorum Su...
-
Ankylosing spondylitis (AS) is a systemic autoimmune disease mainly affecting the lumbar spine and sacroiliac joints, and exhibits periphera...
-
Abstract An electrochemical DNA biosensor based on a G-quadruplex (G4) for the sensitive determination of Pb 2+ was reported using a carb...
-
A drug first designed to prevent cancer cells from multiplying has a second effect: it switches immune cells that turn down the body's a...
-
The majority of hematologist-oncologists who use the social media platform Twitter had some financial conflict of interest, according to new...
-
Contact Dermatitis Early View Online Version of Record before inclusion in an issue ORIGINAL ARTICLESAllergic... Contact Dermatitis Early V...
-
Governments of all political persuasions over the past 20 years have made bold promises to reform the way social care is funded. All have di...
-
In the Original Investigation titled “Yield Strength Testing in Human Cadaver Nasal Septal Cartilage and L-Strut Constructs,” published in t...
-
International Journal of Environmental Research and Public Health, IJERPH, Vol. 16, Pages 3884:... International Journal of Environmental Re...
-
The present study evaluated the anti-inflammatory and analgesic effects of the superoxide dismutase mimetic agent tempol in superoxide anion...
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου