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

Mrosek, Michael; Labeit, Dietmar; Witt, Stephanie; Heerklotz, Heiko; von Castelmur, Eleonore; Labeit, Siegfried; Mayans, Olga

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

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Date

2007

Authors

Mrosek, Michael

Labeit, Dietmar

Witt, Stephanie

Heerklotz, Heiko

von Castelmur, Eleonore

Labeit, Siegfried

Mayans, Olga

DOI (citable link)

10.1096/fj.06-7644com

Collections

Biologie

Publication type

Journal article

Publication status

Published

Published in

The FASEB Journal ; 21 (2007), 7. - pp. 1383-1392. - ISSN 0892-6638. - eISSN 1530-6860

Abstract

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.

Subject (DDC)

570 Biosciences, Biology

Keywords

elastic filament titin, muscle atrophy, X-ray crystallography, binding studies

Cite This

ISO 690

MROSEK, 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. 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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