Molecular determinants for the recruitment of the ubiquitin-ligase MuRF-1 onto M-line titin

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2007
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Mrosek, Michael
Labeit, Dietmar
Witt, Stephanie
Heerklotz, Heiko
von Castelmur, Eleonore
Labeit, Siegfried
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The FASEB Journal. 2007, 21(7), pp. 1383-1392. ISSN 0892-6638. eISSN 1530-6860. Available under: doi: 10.1096/fj.06-7644com
Zusammenfassung

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 (IgA168-IgA169-FnIIIA170, 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.

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570 Biowissenschaften, Biologie
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elastic filament titin, muscle atrophy, X-ray crystallography, binding studies
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ISO 690MROSEK, Michael, Dietmar LABEIT, Stephanie WITT, Heiko HEERKLOTZ, Eleonore VON CASTELMUR, Siegfried LABEIT, Olga MAYANS, 2007. Molecular determinants for the recruitment of the ubiquitin-ligase MuRF-1 onto M-line titin. In: The FASEB Journal. 2007, 21(7), pp. 1383-1392. ISSN 0892-6638. eISSN 1530-6860. Available under: doi: 10.1096/fj.06-7644com
BibTex
@article{Mrosek2007-05Molec-42022,
  year={2007},
  doi={10.1096/fj.06-7644com},
  title={Molecular determinants for the recruitment of the ubiquitin-ligase MuRF-1 onto M-line titin},
  number={7},
  volume={21},
  issn={0892-6638},
  journal={The FASEB Journal},
  pages={1383--1392},
  author={Mrosek, Michael and Labeit, Dietmar and Witt, Stephanie and Heerklotz, Heiko and von Castelmur, Eleonore and Labeit, Siegfried and Mayans, Olga}
}
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    <dcterms:abstract xml:lang="eng">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&lt;sup&gt;A168&lt;/sup&gt;-Ig&lt;sup&gt;A169&lt;/sup&gt;-FnIII&lt;sup&gt;A170&lt;/sup&gt;, 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.</dcterms:abstract>
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