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Literature summary for 3.6.4.B10 extracted from

  • Roh, S.H.; Kasembeli, M.M.; Galaz-Montoya, J.G.; Chiu, W.; Tweardy, D.J.
    Chaperonin TRiC/CCT recognizes fusion oncoprotein AML1-ETO through subunit-specific interactions (2016), Biophys. J., 110, 2377-2385 .
    View publication on PubMedView publication on EuropePMC
Search for more literature for 3.6.4.B10

Application

Application Comment Organism
drug development the enzyme is a target for the specific treatments of AML1-ETO-positive leukemia. AML1-ETO suppression by small interfering RNAs (siRNAs) supports normal myeloid differentiation of t(8,21)-positive leukemic cells which highlights AML1-ETO as a major clinical target to treat AML. Inhibition of HSP70/90, two major proteostasis regulators, has shown antileukemic effects in AML1-ETO positive cells. Moreover, the mammalian cytosolic chaperonin TRiC (or CCT) modulates the synthesis, folding and activity of AML1-ETO by direct association, primarily through its DNA-binding domain (AML1-175), and that HSP70 promotes this interaction Homo sapiens

Crystallization (Commentary)

Crystallization (Comment) Organism
cryo-specimen preparation of AML-1-ETO DNA-binding domain (AML1-175), with TRiC and Hsp70, and cryo-EM imaging, three-dimensional cryo-EM map reconstruction, modelling, method, overview. TRiC can refold denatured AML1-175 (DBD) and restore its DNA binding activity in vitro. Reconstructed the TRiC-AML1-175 complex forms in the presence of Ni2+-gold nanoparticles capable of binding to the His-tag on AML1-175. Ni-affinity nanogold particles reveal the location of AML1-175 on TRiC Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
cytosol
-
 Homo sapiens 5829
-

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + H2O Homo sapiens
-
 ADP + phosphate
-
 ?

Organism

Organism UniProt Comment Textmining
Homo sapiens P17987 AND P78371 AND P49368 AND P50991 AND P48643 AND P40227 AND Q99832 AND P50990 genes CCT1-8 encoding subunits CCT-alpha, CCT-beta, CCT-gamma, CCT-delta, CCT-epsilon, CCT-zeta-1, CCT-eta, and CCT-theta
-

Purification (Commentary)

Purification (Comment) Organism
native enzyme is purified from HeLa cells by a process including anion exchange chromatography and gel filtration Homo sapiens

Renatured (Commentary)

Renatured (Comment) Organism
TRiC can refold denatured AML1-175 (DBD) and restore its DNA binding activity in vitro. The reconstructed the TRiC-AML1-175 complex is formed in the presence of Ni2+-gold nanoparticles capable of binding to the His-tag on AML1-175. While AML1-175 is folded by TRiC to achieve its native function, ATP hydrolysis does not suffice to trigger its release from the chaperonin Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
HeLa cell
-
 Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + H2O
-
 Homo sapiens ADP + phosphate
-
 ?
additional information chaperonin TRiC/CCT recognizes fusion oncoprotein AML1-ETO through subunit-specific interactions. A folding intermediate of AML1-ETO's DNA-binding domain (AML1-175) forms a stable complex with apo-TRiC. TRiC can refold denatured AML1-175 (DBD) and restore its DNA binding activity in vitro. AML1-175 localizes to specific TRiC subunits, it binds to the apical domains of subunits CCT6 and 8 Homo sapiens ?
-
-

Subunits

Subunits Comment Organism
octamer subunits CCT-alpha, CCT-beta, CCT-gamma, CCT-delta, CCT-epsilon, CCT-zeta-1, CCT-eta, and CCT-theta encoded by genes CCT1-8 Homo sapiens

Synonyms

Synonyms Comment Organism
CCT
-
 Homo sapiens
chaperonin containing TCP1
-
 Homo sapiens
cytosolic chaperonin TRiC
-
 Homo sapiens
T-complex polypeptide-1 ring complex
-
 Homo sapiens
TRiC/CCT
-
 Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
37
-
 assay at Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.5
-
 assay at Homo sapiens

General Information

General Information Comment Organism
additional information while AML1-175 is folded by TRiC to achieve its native function, ATP hydrolysis does not suffice to trigger its release from the chaperonin Homo sapiens
physiological function the essential mammalian cytosolic chaperonin TRiC (T-complex polypeptide-1 ring complex, also known as CCT or chaperonin containing TCP1) is an ATPase with an intricate architecture, which allows it to fold many essential proteins. TRiC substrates include cell cycle regulators, signaling proteins, and cytoskeletal components. TRiC has been suggested to play a critical role in cancer cell development by modulating the folding and activity of client proteins involved in oncogenesis, such as the tumor suppressor proteins Von Hippel-Lindau (VHL) and p53, as well as the oncogenic protein STAT3 and AML1-ETO. AML1-ETO is the translational product of a chimeric gene created by the stable chromosome translocation. It causes acute myeloid leukemia (AML) by dysregulating the expression of genes critical for myeloid cell development and differentiation and has been reported to bind multiple subunits of the mammalian cytosolic chaperonin TRiC (or CCT), primarily through its DNA binding domain (AML1-175). Through these interactions, TRiC plays an important role in the synthesis, folding, and activity of AML1-ETO. The structure reveals that AML1-175 associates directly with a specific subset of TRiC subunits in the open conformation. The mammalian cytosolic chaperonin TRiC (or CCT) modulates the synthesis, folding and activity of AML1-ETO by direct association, primarily through its DNA-binding domain (AML1-175), and that HSP70 promotes this interaction. AML1-ETO relies on the molecular chaperone network to fold and function properly Homo sapiens