PDBsum entry 1gxe

Cytoskeleton

PDB id: 1gxe

Contents

Protein chain

130 a.a. *

* Residue conservation analysis

PDB id:

1gxe

Name:

Cytoskeleton

Title:

Central domain of cardiac myosin binding protein c

Structure:

Myosin binding protein c, cardiac-type. Chain: a. Fragment: domain c5, residues 641-770. Synonym: cardiac mybp-c, c-protein - cardiac muscle isoform. Engineered: yes. Other_details: his-tagged protein

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: heart. Tissue: muscle. Cell: myocyte. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Other_details: cardiac protein

NMR struc:

10 models

Authors:

M.Pfuhl

Key ref:

S.M.Idowu et al. (2003). Structure, stability and dynamics of the central domain of cardiac myosin binding protein C (MyBP-C): implications for multidomain assembly and causes for cardiomyopathy. J Mol Biol, 329, 745-761. PubMed id: 12787675 DOI: 10.1016/S0022-2836(03)00425-X

Date:

03-Apr-02 Release date: 12-Jun-03

Protein chain

Q14896  (MYPC3_HUMAN) -  Myosin-binding protein C, cardiac-type from Homo sapiens

Seq: 1274 a.a.

Struc: 130 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1016/S0022-2836(03)00425-X

J Mol Biol 329:745-761 (2003)

PubMed id: 12787675

Structure, stability and dynamics of the central domain of cardiac myosin binding protein C (MyBP-C): implications for multidomain assembly and causes for cardiomyopathy.

S.M.Idowu, M.Gautel, S.J.Perkins, M.Pfuhl.

ABSTRACT

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.

Selected figure(s)

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.

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.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2003, 329, 745-761) copyright 2003.

Figures were selected by the author.