Department of Biomedicine, University of Bergen, Bergen, Norway.
Centre for Bioinformatics (ZBH), University of Hamburg, Hamburg, Germany.
PLoS One. 2021 May 14;16(5):e0251459. doi: 10.1371/journal.pone.0251459. eCollection 2021.
Synaptic plasticity is vital for brain function and memory formation. One of the key proteins in long-term synaptic plasticity and memory is the activity-regulated cytoskeleton-associated protein (Arc). Mammalian Arc forms virus-like capsid structures in a process requiring the N-terminal domain and contains two C-terminal lobes that are structural homologues to retroviral capsids. Drosophila has two isoforms of Arc, dArc1 and dArc2, with low sequence similarity to mammalian Arc, but lacking a large N-terminal domain. Both dArc isoforms are related to the Ty3/gypsy retrotransposon capsid, consisting of N- and C-terminal lobes. Structures of dArc1, as well as capsids formed by both dArc isoforms, have been recently determined. We carried out structural characterization of the four individual dArc lobe domains. As opposed to the corresponding mammalian Arc lobe domains, which are monomeric, the dArc lobes were all oligomeric in solution, indicating a strong propensity for homophilic interactions. A truncated N-lobe from dArc2 formed a domain-swapped dimer in the crystal structure, resulting in a novel dimer interaction that could be relevant for capsid assembly or other dArc functions. This domain-swapped structure resembles the dimeric protein C of flavivirus capsids, as well as the structure of histones dimers, domain-swapped transcription factors, and membrane-interacting BAK domains. The strong oligomerization properties of the isolated dArc lobe domains explain the ability of dArc to form capsids in the absence of any large N-terminal domain, in contrast to the mammalian protein.
突触可塑性对于大脑功能和记忆形成至关重要。长时程突触可塑性和记忆形成的关键蛋白之一是活性调节细胞骨架相关蛋白（Arc）。哺乳动物 Arc 在需要 N 端结构域的过程中形成类似病毒衣壳的结构，并包含两个与逆转录病毒衣壳结构同源的 C 端结构域。果蝇有两种 Arc 同工型，dArc1 和 dArc2，与哺乳动物 Arc 的序列相似性低，但缺乏大的 N 端结构域。两种 dArc 同工型都与 Ty3/gypsy 逆转录转座子衣壳有关，由 N 端和 C 端结构域组成。最近已经确定了 dArc1 的结构以及两种 dArc 同工型形成的衣壳结构。我们对四个单独的 dArc 结构域进行了结构表征。与相应的哺乳动物 Arc 结构域不同，这些结构域是单体的，dArc 结构域在溶液中都是寡聚的，表明它们具有强烈的同源相互作用倾向。来自 dArc2 的截断 N 端结构域在晶体结构中形成了一个交换二聚体，导致一种新的二聚体相互作用，这可能与衣壳组装或其他 dArc 功能有关。这种结构类似于黄病毒衣壳中二聚体蛋白 C，以及组蛋白二聚体、交换二聚体转录因子和膜相互作用 BAK 结构域的结构。分离的 dArc 结构域的强烈寡聚性质解释了 dArc 在没有任何大的 N 端结构域的情况下形成衣壳的能力，这与哺乳动物蛋白形成鲜明对比。
