John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Research School of Biology, Australian National University, Canberra, Australia.
Protein Sci. 2022 May;31(5):e4311. doi: 10.1002/pro.4311.
Excitation-contraction coupling (ECC) is the physiological process in which an electrical signal originating from the central nervous system is converted into muscle contraction. In skeletal muscle tissue, the key step in the molecular mechanism of ECC initiated by the muscle action potential is the cooperation between two Ca channels, dihydropyridine receptor (DHPR; voltage-dependent L-type calcium channel) and ryanodine receptor 1 (RyR1). These two channels were originally postulated to communicate with each other via direct mechanical interactions; however, the molecular details of this cooperation have remained ambiguous. Recently, it has been proposed that one or more supporting proteins are in fact required for communication of DHPR with RyR1 during the ECC process. One such protein that is increasingly believed to play a role in this interaction is the SH3 and cysteine-rich domain-containing protein 3 (STAC3), which has been proposed to bind a cytosolic portion of the DHPR α subunit known as the II-III loop. In this work, we present direct evidence for an interaction between a small peptide sequence of the II-III loop and several residues within the SH3 domains of STAC3 as well as the neuronal isoform STAC2. Differences in this interaction between STAC3 and STAC2 suggest that STAC3 possesses distinct biophysical features that are potentially important for its physiological interactions with the II-III loop. Therefore, this work demonstrates an isoform-specific interaction between STAC3 and the II-III loop of DHPR and provides novel insights into a putative molecular mechanism behind this association in the skeletal muscle ECC process.
兴奋-收缩偶联（ECC）是一种生理过程，其中源自中枢神经系统的电信号转换为肌肉收缩。在骨骼肌组织中，由肌肉动作电位引发的 ECC 分子机制的关键步骤是两个钙通道二氢吡啶受体（DHPR；电压依赖性 L 型钙通道）和兰尼碱受体 1（RyR1）的协同作用。最初假设这两个通道通过直接的机械相互作用彼此通信；然而，这种合作的分子细节仍然不清楚。最近，有人提出，实际上在 ECC 过程中，DHPR 与 RyR1 的通信需要一种或多种辅助蛋白。越来越多的人认为，一种这样的蛋白是 SH3 和富含半胱氨酸结构域的蛋白 3（STAC3），它被认为与 DHPR 的α亚基的细胞溶质部分即 II-III 环结合。在这项工作中，我们提供了直接证据，证明了 II-III 环的一小段肽序列与 STAC3 的 SH3 结构域内的几个残基以及神经元同工型 STAC2 之间存在相互作用。STAC3 和 STAC2 之间的这种相互作用的差异表明，STAC3 具有独特的物理特性，这对于其与 II-III 环的生理相互作用可能很重要。因此，这项工作证明了 STAC3 与 DHPR 的 II-III 环之间的同工型特异性相互作用，并为骨骼肌 ECC 过程中这种关联的潜在分子机制提供了新的见解。
