Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):14954-9. doi: 10.1073/pnas.1307391110. Epub 2013 Aug 22.
Hereditary spastic paraplegias are inherited neurological disorders characterized by progressive lower-limb spasticity and weakness. Although more than 50 genetic loci are known [spastic gait (SPG)1 to -57], over half of hereditary spastic paraplegia cases are caused by pathogenic mutations in four genes encoding proteins that function in tubular endoplasmic reticulum (ER) network formation: atlastin-1 (SPG3A), spastin (SPG4), reticulon 2 (SPG12), and receptor expression-enhancing protein 1 (SPG31). Here, we show that the SPG33 protein protrudin contains hydrophobic, intramembrane hairpin domains, interacts with tubular ER proteins, and functions in ER morphogenesis by regulating the sheet-to-tubule balance and possibly the density of tubule interconnections. Protrudin also interacts with KIF5 and harbors a Rab-binding domain, a noncanonical FYVE (Fab-1, YGL023, Vps27, and EEA1) domain, and a two phenylalanines in an acidic tract (FFAT) domain and, thus, may also function in the distribution of ER tubules via ER contacts with the plasma membrane or other organelles.
遗传性痉挛性截瘫是一种遗传性神经系统疾病，其特征是进行性下肢痉挛和无力。尽管已知有 50 多个遗传位点[痉挛步态（SPG）1 至 -57]，但超过一半的遗传性痉挛性截瘫病例是由编码在管状内质网（ER）网络形成中起作用的蛋白质的四个基因的致病性突变引起的：atlastin-1（SPG3A）、spastin（SPG4）、reticulon 2（SPG12）和受体表达增强蛋白 1（SPG31）。在这里，我们表明 SPG33 蛋白 protrudin 含有疏水性、跨膜发夹结构域，与管状 ER 蛋白相互作用，并通过调节片层到管状的平衡和可能的管状连接密度来调节 ER 形态发生。Protrudin 还与 KIF5 相互作用，并且含有 Rab 结合结构域、非典型 FYVE（Fab-1、YGL023、Vps27 和 EEA1）结构域和两个在酸性片段中的苯丙氨酸（FFAT）结构域，因此，它也可能通过与质膜或其他细胞器的 ER 接触在 ER 管的分布中发挥作用。
