asim farooq
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Inhibition of TGF Receptors. FKBP12 Binding. Asim Farooq. ASAB - NUST. Introduction. TGF β family plays a central role in controlling tissue development and homeostasis Their activation, signaling and deactivation is carefully co-ordinated - PowerPoint PPT PresentationTRANSCRIPT
Asim Farooq
Inhibition of TGF ReceptorsFKBP12 Binding
ASAB - NUST
Introduction TGFβ family plays a central role in controlling
tissue development and homeostasis Their activation, signaling and deactivation is
carefully co-ordinated Serine Threonine kinases, two subunits(I & II),
having a phosphorylating GS domain, RII is a primary receptor and RI is a signal transducer
Mediator protein is SMAD, which accumulates in nucleus and binds to SNPs and transcriptional regulators
Continued Type I receptors have ability to remain activated
in absence of ligand or type II receptors FKBP12 binds to the intracellular domain of
receptor FKBP12 proteins have prolyl isomerase activity,
bind to the Ca2+/calmodulin-dependent protein phosphatase calcineurin and inhibit its ability to mediate T-cell activation, bind to the ryanodine receptor and the inositol 1,4,5-triphosphate receptor, stabilizing the calcium channeling
Receptor Binding FKBP12 interacts with the GS domain of TBR1 The conserved sequence of binding is
T185TSGSGSGLP Missense mutations abolish the receptor
interaction (L193G & P194K) Mutations other than this does not have any
effect on binding capability FKBP12 recognizes a specific structure within
the GS domain that includes the Leu–Pro motif.
FKBP12 Protects Against Leaky TGF Receptor Activation
Mutations in TBR1 result in elevated signaling Overexpression of FKBP12 results in complete
inhibition of signaling Identification of Leu193–Pro as a FKBP12-
binding site argue that the interaction involves the FKBP12 catalytic site
Mechanism of Inhibition FBKP12 inhibits phosphorylation of TBR-I by
TBR-IIHOW???
Overexpression of FKBP12 inhibits ligand-induced TBR-I phosphorylation, whereas the overexpression of mutants defective in TBR-I binding does not
Rapamycin augments TbR-I phosphorylation and reverses the inhibitory effect of overexpressed FKBP12
Continued… FKBP12 binding to this site is likely to hinder
the entry of the phosphorylation sites into the catalytic center of the TBR-II kinase, thus protecting TBR-I from activation during ligand-independent interactions with TBR-II.
In normal physiological conditions, ligand binding removes FKBP12 and receptor is activated to carry out down stream signaling