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PDBsum entry 1gxe
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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, Stability and dynamics of the central domain of cardiac myosin binding protein c (mybp-C): implications for multidomain assembly and causes for cardiomyopathy.
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Authors
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S.M.Idowu,
M.Gautel,
S.J.Perkins,
M.Pfuhl.
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Ref.
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J Mol Biol, 2003,
329,
745-761.
[DOI no: ]
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PubMed id
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Abstract
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The large multidomain muscle protein myosin binding protein C (MyBP-C) has been
implicated for some time in cardiac disease while until recently little was
known about its structure and function. Here we present a detailed study of the
central domain C5 of the cardiac isoform of MyBP-C. This domain is unusual in
several aspects. Firstly it contains two sizeable insertions compared to the
non-cardiac isoforms. The first insertion comprises the linker between domains
cC4 and cC5 that is elongated by ten amino acid residues, the second insertion
comprises an elongation of the CD-loop in the middle of the domain by
approximately 30 amino acid residues. Secondly two point mutations linked to
familial hypertrophic cardiomyopathy (FHC) have been identified in this domain.
This work shows that the general fold of cC5 is in agreement with the IgI family
of beta-sandwich structures. The long cardiac-specific linker between cC4 and
cC5 is not a linker at all but an integral part of the fold of cC5, as evidenced
by an unfolded mutant in which this segment was removed. The second insertion is
shown to be unstructured, highly dynamic and mostly extended according to NMR
relaxation measurements and analytical ultracentrifugation. The loss of several
key interactions conserved in the CD-loop of the IgI fold is assumed to be
responsible for the low stability of cC5 compared to other IgI domains from
titin and MyBP-C itself. The low thermodynamic stability of cC5 is most evident
in one of the two FHC-linked mutations, N755K (Asn115 in this construct) which
is mainly unfolded with a small proportion of a native-like folded species. In
contrast, the second FHC-linked mutation, R654H (Arg14 in this construct) is as
well folded and stable as the wild-type. This residue is located in the extended
beta-bulge at the N terminus of the protein, pointing towards the surface of the
CFGA' beta-sheet. This position is in agreement with recent data pointing to a
function of Arg654 in an intermolecular interaction with MyBP-C domain cC8.
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Figure 3.
Figure 3. Structure of cC5. (a) Family of ten NMR
structures of cC5. The extended b-bulge can be seen to the left
and the unstructured CD loop covers the bottom right part of the
picture. (b) Average RMSD plotted against the sequence for the
best ten structures. The RMSD values reach a maximum of  vert,
similar 20 Å but are cut off at 10 Å. (c) Secondary
structure cartoon of cC5. The orientation is the same as in (a)
with the N terminus to the top left and the C terminus bottom
left. b-Strands are shown as arrows. The A'CFG sheet is in red,
the BDE-sheet is in blue, loops and turns are in green. The long
CD-loop is truncated after the first and before last few
residues.
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Figure 6.
Figure 6. Results of N relaxation analysis of wild-type cC5
at T=293 K. Shown are the order parameters (S, top) and exchange
contributions to R2 (R, bottom) from the Lipari-Szabo analysis
of H-N T, T and heteronuclear NOE data. The b-strands of cC5 are
indicated below the alignment.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2003,
329,
745-761)
copyright 2003.
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Secondary reference #1
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Title
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Sequence specific resonance assignment of the central domain of cardiac myosin binding protein c (mybp-C).
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Authors
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S.M.Idowu,
M.Gautel,
M.Pfuhl.
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Ref.
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J Biomol Nmr, 2002,
22,
199-200.
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PubMed id
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