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Literature summary for 2.3.2.27 extracted from

  • Stewart, M.; Duncan, E.; Coronado, E.; DaRosa, P.; Pruneda, J.; Brzovic, P.; Klevit, R.
    Tuning BRCA1 and BARD1 activity to investigate RING ubiquitin ligase mechanisms (2017), Protein Sci., 26, 475-483 .
    View publication on PubMedView publication on EuropePMC

Application

Application Comment Organism
medicine hyperactive mutations L51W and K65R are capable of rescuing the ligase activity of two cancer-associated variants, C61G and C64G. BRCA1 that contains both a cancer variation and the hyperactive substitutions activates the E2 Ube2d to build polyubiquitin chains as well as wild-type BRCA1. Both activating substitutions L51W and K65R are necessary to restore activity of the cancer variants to the level seen in wild-type Homo sapiens

Protein Variants

Protein Variants Comment Organism
C53A mutation in Zn2+ coordination site of BARD1, increases E3 ligase activity Homo sapiens
C71A mutation in Zn2+ coordination site of BARD1, increases E3 ligase activity Homo sapiens
I26A/L63A/K65A mutations in BRCA1, complete elimination of BRCA1 activity without disrupting its structure Homo sapiens
K65R activating mutation in BRCA1 Homo sapiens
L51W activating mutation in BRCA1 Homo sapiens
L51W/K65R mutant of BRCA1, much more active than either of the individual activating mutants Homo sapiens
additional information a BARD1 construct where the RING domain of is replaced with a five-residue linker to directly connect the helices that normally flank the RING domain retains the ability to bind and promote BRCA1 E3 ligase activity to levels similar to the wild-type enzyme Homo sapiens

Organism

Organism UniProt Comment Textmining
Homo sapiens P38398 and Q99728 P38398 i.. BRCA1, Q99728 i.e. BARD1
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Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
[E2 ubiquitin-conjugating enzyme Ub2k/Ube2w]-S-ubiquitinyl-L-cysteine + [BRCA1]-L-lysine
-
Homo sapiens [E2 ubiquitin-conjugating enzyme Ube2k/Ube2w]-L-cysteine + [BRCA1]-N6-ubiquitinyl-L-lysine
-
?
[E2 ubiquitin-conjugating enzyme Ubc13/Ube2w]-S-ubiquitinyl-L-cysteine + [BRCA1]-L-lysine
-
Homo sapiens [E2 ubiquitin-conjugating enzyme Ubc13/Ube2w]-L-cysteine + [BRCA1]-N6-ubiquitinyl-L-lysine
-
?
[E2 ubiquitin-conjugating enzyme Ube2e1]-S-ubiquitinyl-L-cysteine + [BRCA1]-L-lysine
-
Homo sapiens [E2 ubiquitin-conjugating enzyme Ube2e1]-L-cysteine + [BRCA1]-N6-ubiquitinyl-L-lysine
-
?
[E2 ubiquitin-conjugating enzyme Ube2w]-S-ubiquitinyl-L-cysteine + [BRCA1]-L-lysine
-
Homo sapiens [E2 ubiquitin-conjugating enzyme Ube2w]-L-cysteine + [BRCA1]-N6-ubiquitinyl-L-lysine
-
?

General Information

General Information Comment Organism
physiological function the identity of residues at specific positions in the RING domain can tune activity levels up or down. Substitutions may create a structurally intact BRCA1/BARD1 heterodimer that is inactive in vitro with all E2 enzymes. Substitutions in BRCA1 or BARD1 RING domains may result in hyperactivity, as both proteins have evolved attenuated activity. Loss of attenuation results in decreased product specificity Homo sapiens