4drj
o-crystal structure of the PPIase domain of FKBP52, Rapamycin and the FRB fragment of mTORo-crystal structure of the PPIase domain of FKBP52, Rapamycin and the FRB fragment of mTOR
Structural highlights
Function[FKBP4_HUMAN] Immunophilin protein with PPIase and co-chaperone activities (By similarity). Component of unligated steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). May play a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors between cytoplasm and nuclear compartments (By similarity). The isomerase activity controls neuronal growth cones via regulation of TRPC1 channel opening. Acts also as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability to promote microtubule assembly. May have a protective role against oxidative stress in mitochondria.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe immunosuppressant and anti-cancer drug rapamycin works by inducing inhibitory protein complexes with the kinase mTOR, an important regulator of growth and proliferation. The obligatory accessory partner of rapamycin is believed to be FKBP12. Here we show that rapamycin complexes of larger FKBP protein family members can tightly bind to mTOR and potently inhibit its kinase activity. Co-crystal structures with FKBP51 and FKBP52 reveal the modified molecular binding mode of these alternative ternary complexes in detail. In cellular model systems, FKBP12 can be functionally replaced by larger FKBPs. When rapamycin dosage is limiting, mTOR inhibition of S6K phosphorylation can be enhanced by FKBP51 overexpression in mammalian cells, whereas FKBP12 is dispensable. FKBP51 could also enable the rapamycin-induced hyperphosphorylation of Akt, which depended on higher FKBP levels compared to rapamycin-induced inhibition of S6K phosphorylation. These insights provide a mechanistic rationale for a preferential mTOR inhibition in specific cells or tissues types by engaging specific FKBP homologs. Large FK506-binding Proteins Shape the Pharmacology of Rapamycin.,Marz AM, Fabian AK, Kozany C, Bracher A, Hausch F Mol Cell Biol. 2013 Jan 28. PMID:23358420[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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