1tnn | pdb_00001tnn
Tertiary structure of an immunoglobulin-like domain from the giant muscle protein titin: a new member of the I set
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] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedBACKGROUND: Titin is a gigantic protein located in the thick filament of vertebrate muscles. The putative functions of titin range from interactions with myosin and other muscle proteins to a role in muscle recoil. Analysis of its complete sequence has shown that titin is a multi-domain protein containing several copies of modules of 100 amino acids each. These are thought to belong to the fibronectin type-III and immunoglobulin superfamilies. So far, a complete structural determination has not been carried out on any of the titin modules. RESULTS: The three-dimensional structure of an immunoglobulin module, located in the M-line of the sarcomere close to the titin C terminus and called 'M5', was determined by multi-dimensional NMR spectroscopy. The structure has the predicted immunoglobulin fold with two beta-sheets packed against each other. Each sheet contains four strands. The structure of M5 belongs to the I (intermediate) set of the immunoglobulin superfamily and is very similar to telokin, which is also found in muscles. Although M5 and telokin have relatively little sequence similarity, the two proteins clearly share the same hydrophobic core. The major difference between telokin and the titin M5 module is the absence of the C' strand in the latter. CONCLUSIONS: The titin domains and several of the immunoglobulin-like domains from other modular muscle proteins are highly conserved at the positions corresponding to the hydrophobic core of M5. Our results indicate that it may be possible to use the structure of M5 as a molecular template to model most of the other immunoglobulin-like domains in muscle titin. Tertiary structure of an immunoglobulin-like domain from the giant muscle protein titin: a new member of the I set.,Pfuhl M, Pastore A Structure. 1995 Apr 15;3(4):391-401. PMID:7613868[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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