5kht
Crystal structure of the N-terminal fragment of tropomyosin isoform Tpm1.1 at 1.5 A resolutionCrystal structure of the N-terminal fragment of tropomyosin isoform Tpm1.1 at 1.5 A resolution
Structural highlights
DiseaseTPM1_HUMAN Left ventricular noncompaction;Familial isolated hypertrophic cardiomyopathy;Familial isolated dilated cardiomyopathy. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionTPM1_HUMAN Binds to actin filaments in muscle and non-muscle cells. Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction. Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments.GCN4_YEAST Is a transcription factor that is responsible for the activation of more than 30 genes required for amino acid or for purine biosynthesis in response to amino acid or purine starvation. Binds and recognize the DNA sequence: 5'-TGA[CG]TCA-3'. Publication Abstract from PubMedThe missense mutation R21H in striated muscle tropomyosin is associated with hypertrophic cardiomyopathy, a genetic cardiac disease and a leading cause of sudden cardiac death in young people. Tropomyosin adopts conformation of a coiled-coil that is critical for regulation of muscle contraction. In this study, we investigated the effects of the R21H mutation on the coiled-coil structure of tropomyosin and its interactions with its binding partners, tropomodulin and leiomodin. Using circular dichroism and isothermal titration calorimetry, we found that the mutation profoundly destabilized the structural integrity of alphaTM1a1-28 Zip, a chimeric peptide containing the first 28 residues of tropomyosin. The mutated alphaTM1a1-28 Zip was still able to interact with tropomodulin and leiomodin. However, the mutation resulted in a approximately 30-fold decrease of alphaTM1a1-28 Zip's binding affinity to leiomodin. We used a crystal structure of alphaTM1a1-28 Zip that we solved at 1.5 A resolution to study the mutation's effect in silico by means of molecular dynamics simulation. The simulation data indicated that while the mutation disrupted alphaTM1a1-28 Zip's coiled-coil structure, most notably from residue Ala18 to residue His31, it may not affect the N-terminal end of tropomyosin. The drastic decrease of alphaTM1a1-28 Zip's affinity to leiomodin caused by the mutation may lead to changes in the dynamics at the pointed end of thin filament. Therefore, the R21H mutation is likely interfering with the regulation of the normal thin filament length essential for proper muscle contraction. This article is protected by copyright. All rights reserved. Structural Destabilization of Tropomyosin Induced by the Cardiomyopathy-linked Mutation R21H.,Ly T, Krieger I, Tolkatchev D, Krone C, Moural T, Samatey FA, Kang C, Kostyukova AS Protein Sci. 2017 Nov 6. doi: 10.1002/pro.3341. PMID:29105867[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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