title: Molecular basis for the fold organization and sarcomeric targeting of the muscle atrogin MuRF1.
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.
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Biosciences Building, Crown Street, Liverpool L69 7ZB, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.forename: Alexander
authors.initials: A
authors.lastname: Gasch
authors.forename: Dayté
authors.initials: D
authors.lastname: Rodriguez
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chami
authors.forename: Muzamil M
authors.initials: MM
authors.lastname: Khan
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Rudolf
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Bibby
authors.forename: Akira
authors.initials: A
authors.lastname: Hanashima
authors.forename: Julijus
authors.initials: J
authors.lastname: Bogomolovas
authors.forename: Eleonore
authors.initials: E
authors.lastname: von Castelmur
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rigden
authors.forename: Isabel
authors.initials: I
authors.lastname: Uson
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
authors.forename: Olga
authors.initials: O
authors.lastname: Mayans
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism / Q000473:pathology; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D012518:Sarcomeres / Q000378:metabolism*; D016415:Sequence Alignment; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D009124:Muscle Proteins; D011994:Recombinant Proteins; D000070584:Tripartite Motif Proteins; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: COS-box; RBCC/TRIM fold; X-ray crystallography; ab initio modelling; coiled-coil; electron microscopy