肌营养不良蛋白 C2A 的可变剪接赋予了钙依赖性和非依赖性的膜修复结合。
Alternate splicing of dysferlin C2A confers Ca²⁺-dependent and Ca²⁺-independent binding for membrane repair.
机构信息
Department of Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth 55812 MN, USA.
出版信息
Structure. 2014 Jan 7;22(1):104-15. doi: 10.1016/j.str.2013.10.001. Epub 2013 Nov 14.
Dysferlin plays a critical role in the Ca²⁺-dependent repair of microlesions that occur in the muscle sarcolemma. Of the seven C2 domains in dysferlin, only C2A is reported to bind both Ca²⁺ and phospholipid, thus acting as a key sensor in membrane repair. Dysferlin C2A exists as two isoforms, the "canonical" C2A and C2A variant 1 (C2Av1). Interestingly, these isoforms have markedly different responses to Ca²⁺ and phospholipid. Structural and thermodynamic analyses are consistent with the canonical C2A domain as a Ca²⁺-dependent, phospholipid-binding domain, whereas C2Av1 would likely be Ca²⁺-independent under physiological conditions. Additionally, both isoforms display remarkably low free energies of stability, indicative of a highly flexible structure. The inverted ligand preference and flexibility for both C2A isoforms suggest the capability for both constitutive and Ca²⁺-regulated effector interactions, an activity that would be essential in its role as a mediator of membrane repair.
肌营养不良蛋白在 Ca²⁺依赖性修复肌细胞膜微损伤中发挥关键作用。在肌营养不良蛋白的七个 C2 结构域中，只有 C2A 被报道同时结合 Ca²⁺和磷脂，因此作为膜修复的关键传感器。肌营养不良蛋白 C2A 存在两种同工型，“典型”的 C2A 和 C2A 变体 1（C2Av1）。有趣的是，这些同工型对 Ca²⁺和磷脂的反应明显不同。结构和热力学分析与典型的 C2A 结构域一致，作为 Ca²⁺依赖性、磷脂结合结构域，而 C2Av1 在生理条件下可能是 Ca²⁺非依赖性的。此外，两种同工型都表现出极低的稳定性自由能，表明其结构高度灵活。两种 C2A 同工型的倒置配体偏好和灵活性表明它们具有组成型和 Ca²⁺调节效应物相互作用的能力，这种活性对于其作为膜修复介质的作用至关重要。
Zotero 插件