PDBsum entry 2v6h

Cell adhesion

PDB id: 2v6h

Contents

Protein chain

104 a.a. *

Waters ×170

* Residue conservation analysis

PDB id:

2v6h

Name:

Cell adhesion

Title:

Crystal structure of the c1 domain of cardiac myosin binding protein-c

Structure:

Myosin-binding protein c, cardiac-type. Chain: a. Fragment: c1 domain, residues 151-258. Synonym: cardiac mybp-c, c-protein, cardiac muscle isoform. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: heart. Tissue: cardiac. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.55Å R-factor: 0.184 R-free: 0.241

Authors:

L.Govata,L.Carpenter,P.C.A.Da Fonseca,J.R.Helliwell,P.J.Rizkallah, E.Flashman,N.E.Chayen,C.Redwood,J.M.Squire

Key ref:

L.Govada et al. (2008). Crystal structure of the C1 domain of cardiac myosin binding protein-C: implications for hypertrophic cardiomyopathy. J Mol Biol, 378, 387-397. PubMed id: 18374358 DOI: 10.1016/j.jmb.2008.02.044

Date:

18-Jul-07 Release date: 22-Jul-08

Protein chain

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

Seq: 1274 a.a.

Struc: 104 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1016/j.jmb.2008.02.044

J Mol Biol 378:387-397 (2008)

PubMed id: 18374358

Crystal structure of the C1 domain of cardiac myosin binding protein-C: implications for hypertrophic cardiomyopathy.

L.Govada, L.Carpenter, P.C.da Fonseca, J.R.Helliwell, P.Rizkallah, E.Flashman, N.E.Chayen, C.Redwood, J.M.Squire.

ABSTRACT

C-protein is a major component of skeletal and cardiac muscle thick filaments. Mutations in the gene encoding cardiac C-protein [cardiac myosin binding protein-C (cMyBP-C)] are one of the principal causes of hypertrophic cardiomyopathy. cMyBP-C is a string of globular domains including eight immunoglobulin-like and three fibronectin-like domains termed C0-C10. It binds to myosin and titin, and probably to actin, and may have both a structural and a regulatory role in muscle function. To help to understand the pathology of the known mutations, we have solved the structure of the immunoglobulin-like C1 domain of MyBP-C by X-ray crystallography to a resolution of 1.55 A. Mutations associated with hypertrophic cardiomyopathy are clustered at one end towards the C-terminus, close to the important C1C2 linker, where they alter the structural integrity of this region and its interactions.

Selected figure(s)

Figure 1.
Fig. 1. (a) Schematic representation of the 11 domains [8 immunoglobulin (Ig) and 3 fibronectin (Fn)] of cardiac MyBP-C. (b) Amino acid residues 1–258 of the N-terminal region C0C1 of cMyBP-C derived from the pET-28a vector DNA, including the hexahistidine tag and a thrombin cleavage site (LVPRGS). The sequence highlighted in orange shows the residues seen in crystals of the C1 structure with the sequence in the Pro-Ala linker disordered. (c) Illustration of the key known HCM mutations in the N-terminal domains C0, C1 and C2 of human cMyBP-C. Also shown is the C1–C2 linker with the LAGGGRRIS insertion that can be phosphorylated (shown in pink) and is reported to bind to myosin S2.^5 (d) Multiple sequence alignment of the C1 domain of MyBP-C from different species. Arrows show key HCM mutation sites D228N, Y237S, H257P and E258K. Sequence alignments were produced using CLUSTALW [www.ebi.ac.uk/clustalw] and displayed using the Jalview alignment editor.^6 (e) Sequence alignment of the N-terminal extension on the ELC of human atrial myosin and the C-terminal end of the cMyBP-C C0 domain together with the Pro-Ala linker between C0 and C1 that follows. The boxed sequences, rich in lysines (blue), are thought to form an actin binding site.^7 Acidic residues are shown in red.

Figure 4.
Fig. 4. (a) Stereo view of the C-terminal region of C1 showing interactions of some of the key residues associated with mutations, particularly Asp 228, Tyr237, Phe233 and Glu258. (c) Alternative stereo view to (a) of the same region of C1 but showing the surface locations of the Asp228 and Glu258 residues where the mutations D228N and E258K occur, which radically alter the surface charge. The overviews in (b) and (d) show the whole C1 domain from the same viewing directions as (a) and (c), respectively. (e and f) Schematic diagrams showing the possible binding of (e) the myosin ELC extension and (f) the N-terminal end of C0 and the Pro-Ala link (PA link) between domains C0 and C1 in cMyBP-C to actin filaments through the actin-binding motif (AB motif) whose sequence is given in Fig. 1e. In (e), coloured in red are the myosin subfragment 2 (S2) and the neck and motor of the myosin head. The myosin ELC and regulatory light chain (RLC) are in orange and the Pro-Ala-rich extension on the ELC (PA link) is in blue. A few actin monomers are shown in grey and a tropomyosin strand (TM) in green. (f) This has the same myosin and actin features as in (e), but here part of cMyBP-C is shown with domains 0, 1, 2, 3, 4 and 5 in yellow, the Pro-Ala-rich linker in blue, and the site of mutations in C1 as a light green patch on C1. The MyBP-C motif between C1 and C2 is shown to have three phosphorylation sites (3P). It is envisaged that the binding of C0 and the AB Motif may occur in resting muscle but will be labile and easily broken.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2008, 378, 387-397) copyright 2008.

Figures were selected by an automated process.