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PDBsum entry 1jm7
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structure of a brca1-Bard1 heterodimeric ring-Ring complex.
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Authors
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P.S.Brzovic,
P.Rajagopal,
D.W.Hoyt,
M.C.King,
R.E.Klevit.
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Ref.
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Nat Struct Biol, 2001,
8,
833-837.
[DOI no: ]
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PubMed id
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Abstract
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The RING domain of the breast and ovarian cancer tumor suppressor BRCA1
interacts with multiple cognate proteins, including the RING protein BARD1.
Proper function of the BRCA1 RING domain is critical, as evidenced by the many
cancer-predisposing mutations found within this domain. We present the solution
structure of the heterodimer formed between the RING domains of BRCA1 and BARD1.
Comparison with the RING homodimer of the V(D)J recombination-activating protein
RAG1 reveals the structural diversity of complexes formed by interactions
between different RING domains. The BRCA1-BARD1 structure provides a model for
its ubiquitin ligase activity, illustrates how the BRCA1 RING domain can be
involved in associations with multiple protein partners and provides a framework
for understanding cancer-causing mutations at the molecular level.
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Figure 3.
Figure 3. Surface comparison and structural overlay of the BRCA1
and cCbl RING domains. a, Contact surface representation of
the BRCA1 -BARD1 heterodimer complex and the linker helix and
RING domain from the cCbl -UbcH7 complex14. The remainder of
cCbl is omitted for clarity. The position on cCbl of the UbcH7
binding groove is labeled. b, Overlay of the BRCA1 (dark gray)
and cCbl (light gray) RING domain secondary structural elements.
C  atoms
from 37 structurally equivalent residues were aligned^31 with an
r.m.s. deviation of 1.58 Å. Side chains of cCbl residues (cyan)
that make van der Waals contacts with UbcH7 (Ile 383, Ala 385,
Cys 404, Ser 407, Trp 408, Pro 417 and Leu 418) and the
corresponding residues of BRCA1 (red) (Ile 26, Leu 28, Cys 47,
Lys 50, Leu 51, Pro 62 and Leu 63) are shown. c, Sequence
alignment of the BRCA1 and cCbl RING domains. cCbl RING residues
involved in binding UbcH7 are highlighted in cyan; the
corresponding residues of BRCA1 are highlighted in red. Zn2+
liganding residues are colored purple.
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Figure 4.
Figure 4. Stereo representation of the BRCA1 -BARD1 RING domain
heterodimer depicting the locations of mutations found within
the BRCA1 (gray) and BARD1 (blue) RING domains8. Sites of
known cancer-predisposing mutations (C24R, C39S/Y, C44F, C47G/F,
C61G and C64G/R/Y) are shown in red. Sites of mutations found as
single occurrences in breast and ovarian cancer patients (R7C,
V11A, I15T, M18T, I21V, I31M, T37V, L52F, L63F, L87V, I89T and
I90T) are shown in black. Two Zn2+-liganding residues, Cys 27 in
site I and His 41 in site II (green), have not yet been
identified as mutations in cancer patients. No mutations within
the RING domain of BARD1 have yet been discovered in cancer
patients.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2001,
8,
833-837)
copyright 2001.
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