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| | ==Crystal structure of the N-terminal fragment of tropomyosin isoform Tpm1.1 at 1.5 A resolution== | | ==Crystal structure of the N-terminal fragment of tropomyosin isoform Tpm1.1 at 1.5 A resolution== |
| - | <StructureSection load='5kht' size='340' side='right' caption='[[5kht]], [[Resolution|resolution]] 1.50Å' scene=''> | + | <StructureSection load='5kht' size='340' side='right'caption='[[5kht]], [[Resolution|resolution]] 1.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5kht]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KHT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KHT FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5kht]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_S288C Saccharomyces cerevisiae S288C]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KHT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KHT FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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]] 1.4964Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GCN4, AAS3, ARG9, YEL009C ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5kht FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kht OCA], [http://pdbe.org/5kht PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kht RCSB], [http://www.ebi.ac.uk/pdbsum/5kht PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kht 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=5kht FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kht OCA], [https://pdbe.org/5kht PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5kht RCSB], [https://www.ebi.ac.uk/pdbsum/5kht PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5kht ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/TPM1_HUMAN TPM1_HUMAN]] Left ventricular noncompaction;Familial isolated hypertrophic cardiomyopathy;Familial isolated dilated cardiomyopathy. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/TPM1_HUMAN TPM1_HUMAN] Left ventricular noncompaction;Familial isolated hypertrophic cardiomyopathy;Familial isolated dilated cardiomyopathy. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TPM1_HUMAN TPM1_HUMAN]] Binds to actin filaments in muscle and non-muscle cells. Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction. Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments. | + | [https://www.uniprot.org/uniprot/TPM1_HUMAN TPM1_HUMAN] Binds to actin filaments in muscle and non-muscle cells. Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction. Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments.[https://www.uniprot.org/uniprot/GCN4_YEAST GCN4_YEAST] Is a transcription factor that is responsible for the activation of more than 30 genes required for amino acid or for purine biosynthesis in response to amino acid or purine starvation. Binds and recognize the DNA sequence: 5'-TGA[CG]TCA-3'. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Kostyukova, A S]] | + | [[Category: Large Structures]] |
| - | [[Category: Krieger, I]] | + | [[Category: Saccharomyces cerevisiae S288C]] |
| - | [[Category: Samatey, F A]] | + | [[Category: Kostyukova AS]] |
| - | [[Category: Tolkatchev, D]] | + | [[Category: Krieger I]] |
| - | [[Category: Yoon, Y H]] | + | [[Category: Samatey FA]] |
| - | [[Category: Actin-binding protein]] | + | [[Category: Tolkatchev D]] |
| - | [[Category: Coiled coil]] | + | [[Category: Yoon Y-H]] |
| - | [[Category: Tropomyosin]]
| + | |
| Structural highlights
Disease
TPM1_HUMAN Left ventricular noncompaction;Familial isolated hypertrophic cardiomyopathy;Familial isolated dilated cardiomyopathy. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
Function
TPM1_HUMAN Binds to actin filaments in muscle and non-muscle cells. Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction. Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments.GCN4_YEAST Is a transcription factor that is responsible for the activation of more than 30 genes required for amino acid or for purine biosynthesis in response to amino acid or purine starvation. Binds and recognize the DNA sequence: 5'-TGA[CG]TCA-3'.
Publication Abstract from PubMed
The missense mutation R21H in striated muscle tropomyosin is associated with hypertrophic cardiomyopathy, a genetic cardiac disease and a leading cause of sudden cardiac death in young people. Tropomyosin adopts conformation of a coiled-coil that is critical for regulation of muscle contraction. In this study, we investigated the effects of the R21H mutation on the coiled-coil structure of tropomyosin and its interactions with its binding partners, tropomodulin and leiomodin. Using circular dichroism and isothermal titration calorimetry, we found that the mutation profoundly destabilized the structural integrity of alphaTM1a1-28 Zip, a chimeric peptide containing the first 28 residues of tropomyosin. The mutated alphaTM1a1-28 Zip was still able to interact with tropomodulin and leiomodin. However, the mutation resulted in a approximately 30-fold decrease of alphaTM1a1-28 Zip's binding affinity to leiomodin. We used a crystal structure of alphaTM1a1-28 Zip that we solved at 1.5 A resolution to study the mutation's effect in silico by means of molecular dynamics simulation. The simulation data indicated that while the mutation disrupted alphaTM1a1-28 Zip's coiled-coil structure, most notably from residue Ala18 to residue His31, it may not affect the N-terminal end of tropomyosin. The drastic decrease of alphaTM1a1-28 Zip's affinity to leiomodin caused by the mutation may lead to changes in the dynamics at the pointed end of thin filament. Therefore, the R21H mutation is likely interfering with the regulation of the normal thin filament length essential for proper muscle contraction. This article is protected by copyright. All rights reserved.
Structural Destabilization of Tropomyosin Induced by the Cardiomyopathy-linked Mutation R21H.,Ly T, Krieger I, Tolkatchev D, Krone C, Moural T, Samatey FA, Kang C, Kostyukova AS Protein Sci. 2017 Nov 6. doi: 10.1002/pro.3341. PMID:29105867[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ly T, Krieger I, Tolkatchev D, Krone C, Moural T, Samatey FA, Kang C, Kostyukova AS. Structural Destabilization of Tropomyosin Induced by the Cardiomyopathy-linked Mutation R21H. Protein Sci. 2017 Nov 6. doi: 10.1002/pro.3341. PMID:29105867 doi:http://dx.doi.org/10.1002/pro.3341
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