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Molecular determina...
Molecular determinants for the recruitment of the ubiquitin-ligase MuRF-1 onto M-line titin.
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- Mrosek, Michael (författare)
- Division of Structural Biology, Biozentrum, University of Basel, Basel, Switzerland
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- Labeit, Dietmar (författare)
- Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, Mannheim, Germany
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- Witt, Stephanie (författare)
- Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, Mannheim, Germany
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- Heerklotz, Heiko (författare)
- Chemical Biophysics, Biozentrum, University of Basel, Basel, Switzerland
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- von Castelmur, Eleonore (författare)
- Division of Structural Biology, Biozentrum, University of Basel, Basel, Switzerland
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- Labeit, Siegfried (författare)
- Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, Mannheim, Germany
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- Mayans, Olga (författare)
- Division of Structural Biology, Biozentrum, University of Basel, Basel, Switzerland
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(creator_code:org_t)
- 2007-01-10
- 2007
- Engelska.
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 21:7, s. 1383-1392
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences (hsv//eng)
Nyckelord
- elastic filament titin
- muscle atrophy
- X-ray crystallography
- binding studies
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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