title: Single molecule force spectroscopy on titin implicates immunoglobulin domain stability as a cardiac disease mechanism.
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.
authors.affiliation: Department of Physics, University of Arizona, Tucson, Arizona 85724, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Anderson
authors.forename: Julius
authors.initials: J
authors.lastname: Bogomolovas
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism; D064211:Connectin; D006331:Heart Diseases / Q000378:metabolism*; D007136:Immunoglobulins / Q000737:chemistry*; D007700:Kinetics; D016013:Likelihood Functions; D051379:Mice; D018625:Microscopy, Atomic Force / Q000379:methods*; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D009124:Muscle Proteins / Q000737:chemistry*; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D011489:Protein Denaturation; D015202:Protein Engineering / Q000379:methods; D017510:Protein Folding; D011494:Protein Kinases / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D012518:Sarcomeres / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D064211:Connectin; D007136:Immunoglobulins; D009124:Muscle Proteins; D011494:Protein Kinases