PDBsum entry 2mle

Metal binding protein

PDB id: 2mle

Contents

Protein chain

72 a.a.

Metals

_CA ×2

PDB id:

2mle

Name:

Metal binding protein

Title:

Nmr structure of thE C-domain of troponin c bound to the anchoring region of troponin i

Structure:

Troponin c, slow skeletal and cardiac muscles. Chain: c. Fragment: unp residues 91-161. Synonym: tn-c. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: tnnc1, tnnc. Expressed in: escherichia coli. Expression_system_taxid: 469008.

NMR struc:

20 models

Authors:

I.M.Robertson,O.K.Baryshnikova,P.Mercier,B.D.Sykes

Key ref:

O.K.Baryshnikova et al. (2008). The dilated cardiomyopathy G159D mutation in cardiac troponin C weakens the anchoring interaction with troponin I. Biochemistry, 47, 10950-10960. PubMed id: 18803402

Date:

26-Feb-14 Release date: 12-Mar-14

Protein chain

P63316  (TNNC1_HUMAN) -  Troponin C, slow skeletal and cardiac muscles from Homo sapiens

Seq: 161 a.a.

Struc: 72 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Biochemistry 47:10950-10960 (2008)

PubMed id: 18803402

The dilated cardiomyopathy G159D mutation in cardiac troponin C weakens the anchoring interaction with troponin I.

O.K.Baryshnikova, I.M.Robertson, P.Mercier, B.D.Sykes.

ABSTRACT

NMR spectroscopy has been employed to elucidate the molecular consequences of the DCM G159D mutation on the structure and dynamics of troponin C, and its interaction with troponin I (TnI). Since the molecular effects of human mutations are often subtle, all NMR experiments were conducted as direct side-by-side comparisons of the wild-type C-domain of troponin C (cCTnC) and the mutant protein, G159D. With the mutation, the affinity toward the anchoring region of cTnI (cTnI 34-71) was reduced ( K D = 3.0 +/- 0.6 microM) compared to that of the wild type ( K D < 1 microM). Overall, the structure and dynamics of the G159D.cTnI 34-71 complex were very similar to those of the cCTnC.cTnI 34-71 complex. There were, however, significant changes in the (1)H, (13)C, and (15)N NMR chemical shifts, especially for the residues in direct contact with cTnI 34-71, and the changes in NOE connectivity patterns between the G159D.cTnI 34-71 and cCTnC.cTnI 34-71 complexes. Thus, the most parsimonious hypothesis is that the development of disease results from the poor anchoring of cTnI to cCTnC, with the resulting increase in the level of acto-myosin inhibition in agreement with physiological data. Another possibility is that long-range electrostatic interactions affect the binding of the inhibitory and switch regions of cTnI (cTnI 128-147 and cTnI 147-163) and/or the cardiac specific N-terminus of cTnI (cTnI 1-29) to the N-domain of cTnC. These important interactions are all spatially close in the X-ray structure of the cardiac TnC core.