6h4l | pdb_00006h4l
Structure of Titin M4 trigonal form
Structural highlights
Disease[TITIN_HUMAN] Defects in TTN are the cause of hereditary myopathy with early respiratory failure (HMERF) [MIM:603689]; also known as Edstrom myopathy. HMERF is an autosomal dominant, adult-onset myopathy with early respiratory muscle involvement.[1] Defects in TTN are the cause of familial hypertrophic cardiomyopathy type 9 (CMH9) [MIM:613765]. Familial hypertrophic cardiomyopathy is a hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.[2] Defects in TTN are the cause of cardiomyopathy dilated type 1G (CMD1G) [MIM:604145]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.[3] [4] [5] Defects in TTN are the cause of tardive tibial muscular dystrophy (TMD) [MIM:600334]; also known as Udd myopathy. TMD is an autosomal dominant, late-onset distal myopathy. Muscle weakness and atrophy are usually confined to the anterior compartment of the lower leg, in particular the tibialis anterior muscle. Clinical symptoms usually occur at age 35-45 years or much later.[6] [7] Defects in TTN are the cause of limb-girdle muscular dystrophy type 2J (LGMD2J) [MIM:608807]. LGMD2J is an autosomal recessive degenerative myopathy characterized by progressive weakness of the pelvic and shoulder girdle muscles. Severe disability is observed within 20 years of onset. Defects in TTN are the cause of early-onset myopathy with fatal cardiomyopathy (EOMFC) [MIM:611705]. Early-onset myopathies are inherited muscle disorders that manifest typically from birth or infancy with hypotonia, muscle weakness, and delayed motor development. EOMFC is a titinopathy that, in contrast with the previously described examples, involves both heart and skeletal muscle, has a congenital onset, and is purely recessive. This phenotype is due to homozygous out-of-frame TTN deletions, which lead to a total absence of titin's C-terminal end from striated muscles and to secondary CAPN3 depletion.[8] Function[TITIN_HUMAN] Key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. The size and extensibility of the cross-links are the main determinants of sarcomere extensibility properties of muscle. In non-muscle cells, seems to play a role in chromosome condensation and chromosome segregation during mitosis. Might link the lamina network to chromatin or nuclear actin, or both during interphase.[9] Publication Abstract from PubMedIn striated muscles, molecular filaments are largely composed of long protein chains with extensive arrays of identically folded domains, referred to as "beads-on-a-string". It remains a largely unresolved question how these domains have developed a unique molecular profile such that each carries out a distinct function without false-positive readout. This study focuses on the M-band segment of the sarcomeric protein titin, which comprises ten identically folded immunoglobulin domains. Comparative analysis of high-resolution structures of six of these domains M1, M3, M4, M5, M7, and M10 reveals considerable structural diversity within three distinct loops and a non-conserved pattern of exposed cysteines. Our data allow to structurally interpreting distinct pathological readouts that result from titinopathy-associated variants. Our findings support general principles that could be used to identify individual structural/functional profiles of hundreds of identically folded protein domains within the sarcomere and other densely crowded cellular environments. Structural diversity in the atomic resolution 3D fingerprint of the titin M-band segment.,Chatziefthimiou SD, Hornburg P, Sauer F, Mueller S, Ugurlar D, Xu ER, Wilmanns M PLoS One. 2019 Dec 19;14(12):e0226693. doi: 10.1371/journal.pone.0226693., eCollection 2019. PMID:31856237[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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