Perland Emelie, Hellsten Sofie V, Schweizer Nadine, Arapi Vasiliki, Rezayee Fatemah, Bushra Mona, Fredriksson Robert
Molecular Neuropharmacology, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
PLoS One. 2017 Oct 19;12(10):e0186325. doi: 10.1371/journal.pone.0186325. eCollection 2017.
Out of the 430 known solute carriers (SLC) in humans, 30% are still orphan transporters regarding structure, distribution or function. Approximately one third of all SLCs belong to the evolutionary conserved and functionally diverse Major Facilitator Superfamily (MFS). Here, we studied the orphan proteins, MFSD4A and MFSD9, which are atypical SLCs of MFS type. Hidden Markov Models were used to identify orthologues in several vertebrates, and human MFSD4A and MFSD9 share high sequence identity with their identified orthologues. MFSD4A and MFSD9 also shared more than 20% sequence identity with other phylogenetically related SLC and MFSD proteins, allowing new family clustering. Homology models displayed 12 transmembrane segments for both proteins, which were predicted to fold into a transporter-shaped structure. Furthermore, we analysed the location of MFSD4A and MFSD9 in adult mouse brain using immunohistochemistry, showing abundant neuronal protein staining. As MFSD4A and MFSD9 are plausible transporters expressed in food regulatory brain areas, we monitored transcriptional changes in several mouse brain areas after 24 hours food-deprivation and eight weeks of high-fat diet, showing that both genes were affected by altered food intake in vivo. In conclusion, we propose MFSD4A and MFSD9 to be novel transporters, belonging to disparate SLC families. Both proteins were located to neurons in mouse brain, and their mRNA expression levels were affected by the diet.
在人类已知的430种溶质载体（SLC）中，30%在结构、分布或功能方面仍属于孤儿转运蛋白。所有SLC中约三分之一属于进化上保守且功能多样的主要易化子超家族（MFS）。在此，我们研究了孤儿蛋白MFSD4A和MFSD9，它们是MFS类型的非典型SLC。使用隐马尔可夫模型在几种脊椎动物中鉴定直系同源物，人类MFSD4A和MFSD9与其鉴定出的直系同源物具有高度的序列同一性。MFSD4A和MFSD9与其他系统发育相关的SLC和MFSD蛋白也具有超过20%的序列同一性，从而允许进行新的家族聚类。同源模型显示这两种蛋白都有12个跨膜片段，预计会折叠成转运蛋白形状的结构。此外，我们使用免疫组织化学分析了MFSD4A和MFSD9在成年小鼠大脑中的定位，显示出丰富的神经元蛋白染色。由于MFSD4A和MFSD9可能是在食物调节脑区表达的转运蛋白，我们监测了24小时禁食和八周高脂饮食后几种小鼠脑区的转录变化，结果表明这两个基因在体内均受食物摄入量改变的影响。总之，我们提出MFSD4A和MFSD9是新型转运蛋白，属于不同的SLC家族。这两种蛋白都定位于小鼠大脑中的神经元，并且它们的mRNA表达水平受饮食影响。
