E3 ligases occupy a central place in the enzymatic
cascade leading to protein ubiquitylation
E3 ligase families and modes of
substrate recognition in cells
E3 ligases recognize their physiological targets
through short sequence motifs referred to as degrons.
Degrons can be constitutively accessible to an E3
ligase or formed only upon posttranslational modification.
While many degrons are linear sequence
motifs, structural degrons require a folded protein
domain.
(A) The HECT (homologous to E6-AP C terminus),
RBR (RING-in between-RING), and RCR (RING Cys
relay) E3 ligases possess a catalytic Cys residue that
is charged with ubiquitin by an E2 enzyme.
The E3 ligase then catalyzes substrate modification
(B) E3 ligases of the RING (really interesting new
gene) family bind both a charged E2 enzyme and a
substrate and promote transfer of ubiquitin from the
active site of the E2 directly onto the substrate.
The Cullin-RING ligases are modular RING-family E3 ligases
that utilize exchangeable adaptor proteins to
recruit specific substrates.
E3 ligases recognize their targets through specific motifs referred to as degrons are linear sequence stretches that are constitutively accessible to the E3 ligase. Other degrons require posttranslational modifications, such as phosphorylation
SCFFBXL17
degrades BTB dimers with wrong or mutant subunits, while it leaves active homodimers intact
CHIP
the carboxyl terminus of Hsc70-interacting protein or CHIP, which is a chaperone-associated Ubox-containing E3 ligase. CHIP interacts and ubiquitinates c-Myc, thus targeting it for proteasome-mediated degradation, the interaction between CHIP and c-Myc depends on the N-terminally located tetratricopeptide repeats of CHIP, which has been implicated as a chaperone-binding motif. Inhibition of Hsp90 chaperone activity by 17-N-allylamino-17-demethoxygeldanamycin reduces c-Myc protein level. We found that the association between CHIP and c-Myc is dependent on the chaperones; particularly Hsp70. CHIP antagonizes the transcriptional activity of c-Myc and decreases the abundance of the transcripts of its target genes. Overall, CHIP-knockdown increases malignant behavior of C6 glioma cells.
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