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| [[Image:2nzi.gif|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_2nzi| PDB=2nzi | SCENE= }} | | {{STRUCTURE_2nzi| PDB=2nzi | SCENE= }} |
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| '''Crystal structure of domains A168-A170 from titin'''
| | ===Crystal structure of domains A168-A170 from titin=== |
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| ==Overview==
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| Titin forms an intrasarcomeric filament system in vertebrate striated muscle, which has elastic and signaling properties and is thereby central to mechanotransduction. Near its C-terminus and directly preceding a kinase domain, titin contains a conserved pattern of Ig and FnIII modules (Ig(A168)-Ig(A169)-FnIII(A170), hereby A168-A170) that recruits the E3 ubiquitin-ligase MuRF-1 to the filament. This interaction is thought to regulate myofibril turnover and the trophic state of muscle. We have elucidated the crystal structure of A168-A170, characterized MuRF-1 variants by circular dichroism (CD) and SEC-MALS, and studied the interaction of both components by isothermal calorimetry, SPOTS blots, and pull-down assays. This has led to the identification of the molecular determinants of the binding. A168-A170 shows an extended, rigid architecture, which is characterized by a shallow surface groove that spans its full length and a distinct loop protrusion in its middle point. In MuRF-1, a C-terminal helical domain is sufficient to bind A168-A170 with high affinity. This helical region predictably docks into the surface groove of A168-A170. Furthermore, pull-down assays demonstrate that the loop protrusion in A168-A170 is a key mediator of MuRF-1 recognition. Our findings indicate that this region of titin could serve as a target to attempt therapeutic inhibition of MuRF-1-mediated muscle turnover, where binding of small molecules to its distinctive structural features could block MuRF-1 access.
| | The line below this paragraph, {{ABSTRACT_PUBMED_17215480}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 17215480 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_17215480}} |
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| ==Disease== | | ==Disease== |
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| [[Category: Fniii-domain]] | | [[Category: Fniii-domain]] |
| [[Category: Ig-domain]] | | [[Category: Ig-domain]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 10:07:09 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 20:20:22 2008'' |
