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Single molecule force spectroscopy on titin implicates immunoglobulin domain stability as a cardiac disease mechanism.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2013 Feb 22; Vol. 288 (8), pp. 5303-15. Date of Electronic Publication: 2013 Jan 06. - Publication Year :
- 2013
-
Abstract
- Titin plays crucial roles in sarcomere organization and cardiac elasticity by acting as an intrasarcomeric molecular spring. A mutation in the tenth Ig-like domain of titin's spring region is associated with arrhythmogenic cardiomyopathy, a disease characterized by ventricular arrhythmias leading to cardiac arrest and sudden death. Titin is the first sarcomeric protein linked to arrhythmogenic cardiomyopathy. To characterize the disease mechanism, we have used atomic force microscopy to directly measure the effects that the disease-linked point mutation (T16I) has on the mechanical and kinetic stability of Ig10 at the single molecule level. The mutation decreases the force needed to unfold Ig10 and increases its rate of unfolding 4-fold. We also found that T16I Ig10 is more prone to degradation, presumably due to compromised local protein structure. Overall, the disease-linked mutation weakens the structural integrity of titin's Ig10 domain and suggests an Ig domain disease mechanism.
- Subjects :
- Amino Acid Sequence
Animals
Cardiomyopathies metabolism
Connectin
Kinetics
Likelihood Functions
Mice
Molecular Sequence Data
Monte Carlo Method
Mutation
Myocardium metabolism
Protein Denaturation
Protein Engineering methods
Protein Folding
Protein Structure, Tertiary
Sarcomeres metabolism
Sequence Homology, Amino Acid
Heart Diseases metabolism
Immunoglobulins chemistry
Microscopy, Atomic Force methods
Muscle Proteins chemistry
Protein Kinases chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 288
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 23297410
- Full Text :
- https://doi.org/10.1074/jbc.M112.401372