1tiu | pdb_00001tiu
TITIN, IG REPEAT 27, NMR, 24 STRUCTURES
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. The giant muscle protein titin forms a filament which spans half of the sarcomere and performs, along its length, quite diverse functions. The region of titin located in the sarcomere I-band is believed to play a major role in extensibility and passive elasticity of muscle. In the I-band, the titin sequence consists mostly of repetitive motifs of tandem immunoglobulin-like (Ig) modules intercalated by a potentially non-globular region. The highly repetitive titin architecture suggests that the molecular basis of its mechanical properties be approached through the characterization of the isolated components of the I-band and their interfaces. In the present paper, we report on the structure determination in solution of a representative Ig module from the I-band (I27) as solved by NMR techniques. RESULTS. The structure of I27 consists of a beta sandwich formed by two four-stranded sheets (named ABED and A'GFC). This fold belongs to the intermediate frame (I frame) of the immunoglobulin superfamily. Comparison of I27 with another titin module from the region located in the M-line (M5) shows that two loops (between the B and C and the F and G strands) are shorter in I27, conferring a less elongated appearance to this structure. Such a feature is specific to the Ig domains in the I-band and might therefore be related to the functions of the protein in this region. The structure of tandem Ig domains as modeled from I27 suggests the presence of hinge regions connecting contiguous modules. CONCLUSIONS. We suggest that titin Ig domains in the I-band function as extensible components of muscle elasticity by stretching the hinge regions. Immunoglobulin-like modules from titin I-band: extensible components of muscle elasticity.,Improta S, Politou AS, Pastore A Structure. 1996 Mar 15;4(3):323-37. PMID:8805538[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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