Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle
Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle
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DOI：
10.1093/hmg/ddn081
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发表时间：
2008-06-15
影响因子：
3.5
通讯作者：
van der Maarel, Silvere M.
中科院分区：
文献类型：
--
作者：
Huang, Yanchao;de Morree, Antoine;van der Maarel, Silvere M.
肌营养不良症包括一组遗传异质性的退行性肌肉疾病，其特征是进行性肌肉萎缩和虚弱。两种形式的肢体带状肌营养不良症，2A和2B，分别由钙蛋白3(CAPN3)和功能障碍蛋白(DYSF)突变引起。虽然CAPN3可能参与肌节重塑，但DYSF被认为在膜修复中发挥作用。CAPN3和参与肌膜下细胞结构和膜修复的AHNAK蛋白在deferlin蛋白复合体中共存，以及骨骼肌中AHNAK蛋白水解性切割片段的存在，使我们研究AHNAK是否可以作为CAPN3的底物。我们在这里证明了AHNAK被CAPN3切割，并表明AHNAK在表达活性CAPN3的细胞中丢失。相反，当钙化症患者骨骼肌中的Calain 3缺陷时，AHNAK就会积聚。此外，我们还证明了被CAPN3切割的AHNAK片段已经失去了对去铁蛋白的亲和力。因此，我们的发现揭示了CAPN3在调节deferlin蛋白复合体中的新的生理作用，从而提示了这两种疾病之间的相互联系。
Muscular dystrophies comprise a genetically heterogeneous group of degenerative muscle disorders characterized by progressive muscle wasting and weakness. Two forms of limb-girdle muscular dystrophy, 2A and 2B, are caused by mutations in calpain 3 (CAPN3) and dysferlin (DYSF), respectively. While CAPN3 may be involved in sarcomere remodeling, DYSF is proposed to play a role in membrane repair. The coexistence of CAPN3 and AHNAK, a protein involved in subsarcolemmal cytoarchitecture and membrane repair, in the dysferlin protein complex and the presence of proteolytic cleavage fragments of AHNAK in skeletal muscle led us to investigate whether AHNAK can act as substrate for CAPN3. We here demonstrate that AHNAK is cleaved by CAPN3 and show that AHNAK is lost in cells expressing active CAPN3. Conversely, AHNAK accumulates when calpain 3 is defective in skeletal muscle of calpainopathy patients. Moreover, we demonstrate that AHNAK fragments cleaved by CAPN3 have lost their affinity for dysferlin. Thus, our findings suggest interconnectivity between both diseases by revealing a novel physiological role for CAPN3 in regulating the dysferlin protein complex.