8bw6: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[8bw6]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8BW6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BW6 FirstGlance]. <br>
<table><tr><td colspan='2'>[[8bw6]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8BW6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BW6 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8bw6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bw6 OCA], [https://pdbe.org/8bw6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bw6 RCSB], [https://www.ebi.ac.uk/pdbsum/8bw6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bw6 ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8bw6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bw6 OCA], [https://pdbe.org/8bw6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bw6 RCSB], [https://www.ebi.ac.uk/pdbsum/8bw6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bw6 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
<div style="background-color:#fffaf0;">
[https://www.uniprot.org/uniprot/TITIN_HUMAN TITIN_HUMAN] Defects in TTN are the cause of hereditary myopathy with early respiratory failure (HMERF) [MIM:[https://omim.org/entry/603689 603689]; also known as Edstrom myopathy. HMERF is an autosomal dominant, adult-onset myopathy with early respiratory muscle involvement.<ref>PMID:15802564</ref>  Defects in TTN are the cause of familial hypertrophic cardiomyopathy type 9 (CMH9) [MIM:[https://omim.org/entry/613765 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.<ref>PMID:10462489</ref>  Defects in TTN are the cause of cardiomyopathy dilated type 1G (CMD1G) [MIM:[https://omim.org/entry/604145 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.<ref>PMID:11846417</ref> <ref>PMID:11788824</ref> <ref>PMID:16465475</ref>  Defects in TTN are the cause of tardive tibial muscular dystrophy (TMD) [MIM:[https://omim.org/entry/600334 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.<ref>PMID:12145747</ref> <ref>PMID:12891679</ref>  Defects in TTN are the cause of limb-girdle muscular dystrophy type 2J (LGMD2J) [MIM:[https://omim.org/entry/608807 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:[https://omim.org/entry/611705 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.<ref>PMID:17444505</ref>  
== Publication Abstract from PubMed ==
== Function ==
Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction (NJ) of skeletal muscles. The major MG autoantigen is nicotinic acetylcholine receptor. Other autoantigens at the NJ include MuSK, LRP4 and agrin. Autoantibodies to the intra-sarcomeric striated muscle-specific gigantic protein titin, although not directed to the NJ, are invaluable biomarkers for thymoma and MG disease severity. Thymus and thymoma are critical in MG mechanisms and management. Titin autoantibodies bind to a 30 KDa titin segment, the main immunogenic region (MIR), consisting of an Ig-FnIII-FnIII 3-domain tandem, termed I109-I111. In this work, we further resolved the localization of titin epitope(s) to facilitate the development of more specific anti-titin diagnostics. For this, we expressed protein samples corresponding to 8 MIR and non-MIR titin fragments and tested 77 anti-titin sera for antibody binding using ELISA, competition experiments and Western blots. All anti-MIR antibodies were bound exclusively to the central MIR domain, I110, and to its containing titin segments. Most antibodies were bound also to SDS-denatured I110 on Western blots, suggesting that their epitope(s) are non-conformational. No significant difference was observed between thymoma and non-thymoma patients or between early- and late-onset MG. In addition, atomic 3D-structures of the MIR and its subcomponents were elucidated using X-ray crystallography. These immunological and structural data will allow further studies into the atomic determinants underlying titin-based autoimmunity, improved diagnostics and how to eventually treat titin autoimmunity associated co-morbidities.
[https://www.uniprot.org/uniprot/TITIN_HUMAN 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.<ref>PMID:9804419</ref>  
 
Immunological and Structural Characterization of Titin Main Immunogenic Region; I110 Domain Is the Target of Titin Antibodies in Myasthenia Gravis.,Stergiou C, Williams R, Fleming JR, Zouvelou V, Ninou E, Andreetta F, Rinaldi E, Simoncini O, Mantegazza R, Bogomolovas J, Tzartos J, Labeit S, Mayans O, Tzartos S Biomedicines. 2023 Feb 3;11(2):449. doi: 10.3390/biomedicines11020449. PMID:36830985<ref>PMID:36830985</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8bw6" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Titin 3D structures|Titin 3D structures]]
== References ==
== References ==
<references/>
<references/>

Latest revision as of 12:30, 17 October 2024

Titin FnIII-domain I110 (I/A6) from the MIR regionTitin FnIII-domain I110 (I/A6) from the MIR region

Structural highlights

8bw6 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.95Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction (NJ) of skeletal muscles. The major MG autoantigen is nicotinic acetylcholine receptor. Other autoantigens at the NJ include MuSK, LRP4 and agrin. Autoantibodies to the intra-sarcomeric striated muscle-specific gigantic protein titin, although not directed to the NJ, are invaluable biomarkers for thymoma and MG disease severity. Thymus and thymoma are critical in MG mechanisms and management. Titin autoantibodies bind to a 30 KDa titin segment, the main immunogenic region (MIR), consisting of an Ig-FnIII-FnIII 3-domain tandem, termed I109-I111. In this work, we further resolved the localization of titin epitope(s) to facilitate the development of more specific anti-titin diagnostics. For this, we expressed protein samples corresponding to 8 MIR and non-MIR titin fragments and tested 77 anti-titin sera for antibody binding using ELISA, competition experiments and Western blots. All anti-MIR antibodies were bound exclusively to the central MIR domain, I110, and to its containing titin segments. Most antibodies were bound also to SDS-denatured I110 on Western blots, suggesting that their epitope(s) are non-conformational. No significant difference was observed between thymoma and non-thymoma patients or between early- and late-onset MG. In addition, atomic 3D-structures of the MIR and its subcomponents were elucidated using X-ray crystallography. These immunological and structural data will allow further studies into the atomic determinants underlying titin-based autoimmunity, improved diagnostics and how to eventually treat titin autoimmunity associated co-morbidities.

Immunological and Structural Characterization of Titin Main Immunogenic Region; I110 Domain Is the Target of Titin Antibodies in Myasthenia Gravis.,Stergiou C, Williams R, Fleming JR, Zouvelou V, Ninou E, Andreetta F, Rinaldi E, Simoncini O, Mantegazza R, Bogomolovas J, Tzartos J, Labeit S, Mayans O, Tzartos S Biomedicines. 2023 Feb 3;11(2):449. doi: 10.3390/biomedicines11020449. PMID:36830985[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Stergiou C, Williams R, Fleming JR, Zouvelou V, Ninou E, Andreetta F, Rinaldi E, Simoncini O, Mantegazza R, Bogomolovas J, Tzartos J, Labeit S, Mayans O, Tzartos S. Immunological and Structural Characterization of Titin Main Immunogenic Region; I110 Domain Is the Target of Titin Antibodies in Myasthenia Gravis. Biomedicines. 2023 Feb 3;11(2):449. PMID:36830985 doi:10.3390/biomedicines11020449

8bw6, resolution 1.95Å

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