Pollegioni Loredano, Piubelli Luciano, Molla Gianluca, Rosini Elena
Dipartimento di Biotecnologie e Scienze della Vita, Università degli Studi dell'Insubria, Varese, Italy.
The Protein Factory, Politecnico di Milano and Università degli studi dell'Insubria, Milan, Italy.
Front Mol Biosci. 2018 Jan 24;5:3. doi: 10.3389/fmolb.2018.00003. eCollection 2018.
pLG72 is a small, primate-specific protein of 153 amino acids. It is the product of the gene, expressed in testis, spinal cord, and brain. The presence of transcript and pLG72 has recurrently been called into question, however mRNA and pLG72 protein levels were higher in blood and brain of patients with schizophrenia than in healthy controls. On the one hand, the SNP rs2391191 corresponding to the R30K substitution in pLG72 was genetically linked to schizophrenia, reduced thickness of the brain cortex in schizophrenia-affected individuals, and altered memory function. Various lines of evidence indicated that pLG72 is a mitochondrial protein, specifically an extrinsic protein bound on the outer membrane. Over the years, pLG72 was proposed to be involved in different functions: (a) overexpression induces mitochondria fragmentation, increasing the numbers of shorter and more mobile ones which could be delivered faster to regions of intense growth and facilitating the dendritic complexity; (b) it might induce oxidative stress by interacting with methionine-R-sulfoxide reductase B2; and (c) it binds and modulates the activity of FMN-containing oxidoreductase of the respiratory complex I. The main role of this protein, however, is related to its binding to the human flavoenzyme D-amino acid oxidase (hDAAO), i.e., the main catabolic enzyme for D-enantiomer of serine. This D-amino acid is a main endogenous coagonist of the N-methyl-D-aspartate type glutamate receptor (NMDAR) involved in main functions such as synaptic plasticity, learning, memory, and excitotoxicity. For this work, we reviewed the recent literature concerning the hDAAO-pLG72 interaction, focusing on the molecular details of the interaction, the effect of hDAAO function and stability, and the cellular effects, especially on D-serine concentration. The main effects related to the pathological R30K substitution are also reported. We have highlighted the gaps in our knowledge of this human protein as well as the relevance of clarifying the molecular details of hDAAO-pLG72 interaction in order to design molecules to modulate hDAAO activity/stability and thus NMDAR function acting at the D-serine cellular level.
pLG72是一种由153个氨基酸组成的小型灵长类特异性蛋白质。它是该基因的产物，在睾丸、脊髓和大脑中表达。然而，转录本和pLG72的存在一直受到质疑，不过精神分裂症患者血液和大脑中的mRNA和pLG72蛋白水平高于健康对照组。一方面，与pLG72中R30K替换相对应的单核苷酸多态性rs2391191与精神分裂症存在遗传关联，精神分裂症患者大脑皮层厚度减小，记忆功能改变。各种证据表明pLG72是一种线粒体蛋白，特别是一种结合在外膜上的外在蛋白。多年来，pLG72被认为参与不同功能：（a）过表达诱导线粒体碎片化，增加更短且更易移动的线粒体数量，这些线粒体可以更快地被输送到生长活跃的区域并促进树突复杂性；（b）它可能通过与蛋氨酸-R-亚砜还原酶B2相互作用诱导氧化应激；（c）它结合并调节呼吸复合体I中含黄素单核苷酸的氧化还原酶的活性。然而，这种蛋白质的主要作用与其与人黄素酶D-氨基酸氧化酶（hDAAO）的结合有关，hDAAO是丝氨酸D-对映体的主要分解代谢酶。这种D-氨基酸是N-甲基-D-天冬氨酸型谷氨酸受体（NMDAR）的主要内源性协同激动剂，参与突触可塑性、学习、记忆和兴奋性毒性等主要功能。在这项工作中，我们回顾了关于hDAAO-pLG72相互作用的最新文献，重点关注相互作用的分子细节、hDAAO功能和稳定性的影响以及细胞效应，特别是对D-丝氨酸浓度的影响。还报道了与病理性R30K替换相关的主要影响。我们强调了我们对这种人类蛋白质认识上的差距，以及阐明hDAAO-pLG72相互作用分子细节的相关性，以便设计分子来调节hDAAO活性/稳定性，从而在D-丝氨酸细胞水平上调节NMDAR功能。
