The ubiquitin-specific protease USP25 interacts with three sarcomeric proteins

The biological functions of the more than one hundred genes coding for deubiquitinating enzymes in the human genome remain mostly unknown. The USP25 gene, located at 21q11.2, encodes three protein isoforms produced by alternative splicing. While two of the isoforms are expressed nearly ubiquituously, the expression of the longer USP25 isoform (USP25m) is restricted to muscular tissues and is upregulated during myogenesis. USP25m interacts with three sarcomeric proteins: actin alpha-1 (ACTA1), filamin C (FLNC), and myosin binding protein C1 (MyBPC1), which are critically involved in muscle differentiation and maintenance, and have been implicated in the pathogenesis of severe myopathies. Biochemical analyses demonstrated that MyBPC1 is a short-lived proteasomal substrate, and its degradation is prevented by over-expression of USP25m but not by other USP25 isoforms. In contrast, ACTA1 and FLNC appear to be stable proteins, indicating that their interaction with USP25m is not related to their turnover rate. Received 7 November 2005; received after revision 7 January 2006; accepted 13 January 2006     

肌小节组装研究进展

肌小节是横纹肌的基本功能单位,是由肌动蛋白、肌球蛋白和各种相关蛋白质组装而成的高度有序的结构。在肌小节组装过程中,Z带、M带以及一系列相关蛋白的正确组装是维持肌肉运动的关键,研究肌小节组成蛋白的折叠和组装机制对于了解肌肉疾病的病因和进行有针对性地治疗非常重要。本文综述了肌小节中的主要组分以及组装过程的研究进展,认为目前仍对肌小节骨架的装配、收缩复合体的功能及肌小节组装相关分子伴侣与疾病的关系等的相关研究不够深入。因此,未来还需从肌球蛋白结合蛋白、肌联蛋白、分子伴侣等与疾病的关系方面开展进一步的研究,为肌肉相关疾病的治疗寻找新的思路和解决办法。     

The muscle ultrastructure: a structural perspective of the sarcomere

Muscle ultrastructure is characterised by a complex arrangement of many protein-protein interactions. The sarcomere is the basic repeating unit of muscle, formed by two transverse filament systems: the thick and thin filaments. While actin and myosin are the main contractile elements of the sarcomere, other proteins act as scaffolds, control ultrastructure composition, regulate muscle contraction, and transmit tension between sarcomeres and hence to the whole myofibril. Elucidation of the structures of muscle proteins by X-ray crystallography and nuclear magnetic resonance spectroscopy has been essential in understanding muscle contraction, enabling us to relate biological to structural information. These structures reveal how components of the muscle interact, how different factors influence conformational changes within these proteins, and how mutant muscle proteins may interfere with the regulatory fine-tuning of the contractile machinery, hence leading to disease in some cases. Here, structures solved within the sarcomere have been reviewed in order to put the numerous components into context.Received 28 June 2004; received after revision 25 July 2004; accepted 28 July 2004