32
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Cardiac Troponin and Tropomyosin: Structural and Cellular Perspectives to Unveil the Hypertrophic Cardiomyopathy Phenotype

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Inherited myopathies affect both skeletal and cardiac muscle and are commonly associated with genetic dysfunctions, leading to the production of anomalous proteins. In cardiomyopathies, mutations frequently occur in sarcomeric genes, but the cause-effect scenario between genetic alterations and pathological processes remains elusive. Hypertrophic cardiomyopathy (HCM) was the first cardiac disease associated with a genetic background. Since the discovery of the first mutation in the β-myosin heavy chain, more than 1400 new mutations in 11 sarcomeric genes have been reported, awarding HCM the title of the “disease of the sarcomere.” The most common macroscopic phenotypes are left ventricle and interventricular septal thickening, but because the clinical profile of this disease is quite heterogeneous, these phenotypes are not suitable for an accurate diagnosis. The development of genomic approaches for clinical investigation allows for diagnostic progress and understanding at the molecular level. Meanwhile, the lack of accurate in vivo models to better comprehend the cellular events triggered by this pathology has become a challenge. Notwithstanding, the imbalance of Ca 2+ concentrations, altered signaling pathways, induction of apoptotic factors, and heart remodeling leading to abnormal anatomy have already been reported. Of note, a misbalance of signaling biomolecules, such as kinases and tumor suppressors (e.g., Akt and p53), seems to participate in apoptotic and fibrotic events. In HCM, structural and cellular information about defective sarcomeric proteins and their altered interactome is emerging but still represents a bottleneck for developing new concepts in basic research and for future therapeutic interventions. This review focuses on the structural and cellular alterations triggered by HCM-causing mutations in troponin and tropomyosin proteins and how structural biology can aid in the discovery of new platforms for therapeutics. We highlight the importance of a better understanding of allosteric communications within these thin-filament proteins to decipher the HCM pathological state.

          Related collections

          Most cited references263

          • Record: found
          • Abstract: not found
          • Article: not found

          Principles that govern the folding of protein chains.

          C ANFINSEN (1973)
            Bookmark
            • Record: found
            • Abstract: not found
            • Article: not found

            Central dogma of molecular biology.

              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Tumor suppressor p53 is a direct transcriptional activator of the human bax gene.

              The bax gene promoter region contains four motifs with homology to consensus p53-binding sites. In cotransfection assays using p53-deficient tumor cell lines, wild-type but not mutant p53 expression plasmids transactivated a reporter gene plasmid that utilized the bax gene promoter to drive transcription of chloramphenicol acetyltransferase. In addition, wild-type p53 transactivated reporter gene constructs containing a heterologous minimal promoter and a 39-bp region from the bax gene promoter in which the p53-binding site consensus sequences reside. Introduction of mutations into the consensus p53-binding site sequences abolished p53 responsiveness of reporter gene plasmids. Wild-type but not mutant p53 protein bound to oligonucleotides corresponding to this region of the bax promoter, based on gel retardation assays. Taken together, the results suggest that bax is a p53 primary-response gene, presumably involved in a p53-regulated pathway for induction of apoptosis.
                Bookmark

                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                23 September 2016
                2016
                : 7
                : 429
                Affiliations
                Programa de Biologia Estrutural, Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil
                Author notes

                Edited by: P. Bryant Chase, Florida State University, USA

                Reviewed by: Brenda Schoffstall, Barry University, USA; Adriano S. Martins, Icahn School of Medicine at Mount Sinai, USA

                *Correspondence: Guilherme A. P. de Oliveira gaugusto@ 123456bioqmed.ufrj.br

                This article was submitted to Striated Muscle Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2016.00429
                5033975
                27721798
                106ddd24-d462-4c86-a52c-c61480f688a4
                Copyright © 2016 Marques and de Oliveira.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 27 July 2016
                : 09 September 2016
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 296, Pages: 25, Words: 23158
                Categories
                Physiology
                Review

                Anatomy & Physiology
                hypertrophic cardiomyopathy,protein dynamics,sarcomeric mutations,thin filament,allostery

                Comments

                Comment on this article