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Molecular basis for the fold organization and sarcomeric targeting of the muscle atrogin MuRF1

DOI: 10.1098/rsob.130172 DOI Help

Authors: Barbara Franke (University of Liverpool) , Alexander Gasch (Universitatsklinikum Mannheim) , Dayte Rodriguez (Instituto de Biologýa Molecular de Barcelona) , Mohamed Chami (University of Basel) , Muzamil M. Khan (Karlsruhe Institute of Technology) , Rudiger Rudolf (Karlsruhe Institute of Technology) , Jaclyn Bibby (University of Liverpool) , Akira Hanashima (Universitatsklinikum Mannheim) , Julijus Bogomolovas (University of Liverpool) , Eleonore Von Castelmur (University of Liverpool) , Daniel J. Rigden (University of Liverpool) , Isabel Uson (Instituto de Biologýa Molecular de Barcelona) , Siegfried Labeit (Universitatsklinikum Mannheim) , Olga Mayans (University of Liverpool)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Open Biology , VOL 4 (3) , PAGES 130172 - 130172

State: Published (Approved)
Published: March 2014

Open Access Open Access

Abstract: MuRF1 is an E3 ubiquitin ligase central to muscle catabolism. It belongs to the TRIM protein family characterized by a tripartite fold of RING, B-box and coiled-coil (CC) motifs, followed by variable C-terminal domains. The CC motif is hypothesized to be responsible for domain organization in the fold as well as for high-order assembly into functional entities. But data on CC from this family that can clarify the structural significance of this motif are scarce. We have characterized the helical region from MuRF1 and show that, contrary to expectations, its CC domain assembles unproductively, being the B2- and COS-boxes in the fold (respectively flanking the CC) that promote a native quaternary structure. In particular, the C-terminal COS-box seemingly forms an α-hairpin that packs against the CC, influencing its dimerization. This shows that a C-terminal variable domain can be tightly integrated within the conserved TRIM fold to modulate its structure and function. Furthermore, data from transfected muscle show that in MuRF1 the COS-box mediates the in vivo targeting of sarcoskeletal structures and points to the pharmacological relevance of the COS domain for treating MuRF1-mediated muscle atrophy.

Journal Keywords: RBCC/TRIM fold; coiled-coil; COS-box; X-ray crystallography; electron microscopy; ab initio modelling

Subject Areas: Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography

Added On: 22/04/2014 15:34

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