Single molecule force spectroscopy on titin implicates immunoglobulin domain stability as a cardiac disease mechanism
| Autor: | Siegfried Labeit, Brian R. Anderson, Henk Granzier, Julius Bogomolovas |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Sarcomeres
Protein Denaturation Protein Folding animal structures Heart Diseases Molecular Sequence Data Immunoglobulins Muscle Proteins Obscurin Immunoglobulin domain Protein degradation Biology Microscopy Atomic Force Protein Engineering Biochemistry Sudden death Mice Protein structure Animals Connectin Amino Acid Sequence Sarcomere organization Molecular Biology Likelihood Functions Sequence Homology Amino Acid Myocardium Cell Biology musculoskeletal system Molecular biology humanities Protein Structure Tertiary Actinin alpha 2 Kinetics embryonic structures Mutation cardiovascular system Biophysics biology.protein Titin Cardiomyopathies tissues Monte Carlo Method Protein Kinases Molecular Biophysics |
| Zdroj: | The Journal of biological chemistry. 288(8) |
| ISSN: | 1083-351X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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