Institute of Integrative Biology, University of Liverpool, Biosciences Building, Crown Street, Liverpool L69 7ZB, UK.
Open Biol. 2014 Mar 26;4(3):130172. doi: 10.1098/rsob.130172.
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.
MuRF1 是一种 E3 泛素连接酶，是肌肉分解代谢的核心。它属于 TRIM 蛋白家族，其特征是由 RING、B-box 和卷曲螺旋（CC）基序组成的三部分折叠，后面跟着可变的 C 末端结构域。CC 基序被假设负责折叠中的结构域组织以及高级别组装成功能实体。但是，关于这个家族中可以阐明该基序结构意义的 CC 数据却很少。我们已经对 MuRF1 的螺旋区域进行了表征，结果表明，与预期相反，其 CC 结构域的组装是无效的，在折叠中（分别位于 CC 的两侧）的 B2-和 COS-盒促进了天然的四级结构。特别是，C 末端 COS-盒似乎形成了一个 α-发夹，与 CC 相吻合，影响其二聚化。这表明 C 末端可变结构域可以紧密整合到保守的 TRIM 折叠中，以调节其结构和功能。此外，来自转染肌肉的实验数据表明，在 MuRF1 中，COS-盒介导了骨骼肌结构的体内靶向，并指出了 COS 结构域在治疗 MuRF1 介导的肌肉萎缩中的药理学相关性。
