Setaluri V
Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Pigment Cell Res. 2000 Jun;13(3):128-34. doi: 10.1034/j.1600-0749.2000.130302.x.
Newly synthesized melanosomal proteins, like many other cellular proteins, traverse through a series of intracellular compartments en route to melanosomes. Entry and exit of proteins through these compartments is orchestrated by cellular sorting machinery that recognize specific sorting signals. Melanosomal membrane proteins begin their intracellular journey upon co-translational importation into the endoplasmic reticulum (ER). The biosynthetic output of tyrosinase, the key melanogenic enzyme, appears to be regulated by quality-control events at the ER, the 'port of entry' to the secretory pathway. Following maturation in the ER and through the Golgi, the sorting of these proteins in the trans-Golgi network for intracellular retention and transport along endosome/lysosome pathway requires cytoplasmically exposed signals. A di-leucine motif, present in the cytoplasmic tails of most melanosomal proteins, and its interaction with adaptor protein (AP) complexes, specifically AP-3, are critical for these events. Defects in sorting signals and the cytosolic components that interact with these signals result in a number of murine coat color phenotypes and cause human pigmentary disorders. Thus, missense or frame-shift mutations that produce truncated tyrosinase lacking the melanosomal sorting signal(s) appear to be responsible for murine platinum coat color phenotypes and a proportion of human oculocutaneous albinism-1; mutations in AP-3 appear to be responsible for the mocha phenotype in mice and Hermansky-Pudlak-like syndrome in man. Additional signals and sorting steps downstream of AP-3 appear to be required for endosomal sorting and targeting proteins to melanosomes. Signals and mechanisms that sequester melanosomal proteins from endosomes/lysosomes are not understood. Potential candidates that mediate such processes include proteins encoded by lyst and pallid genes. The common occurrence of abnormalities in melanosomes in many storage-pool disorders suggests that melanocytes utilize signals, pathways, and mechanisms shared by other proteins and cell types to assemble a number of specialized proteins and produce unique cell-type-specific organelles.
新合成的黑素小体蛋白与许多其他细胞蛋白一样，在前往黑素小体的途中会穿过一系列细胞内区室。蛋白质进出这些区室是由识别特定分选信号的细胞分选机制精心安排的。黑素小体膜蛋白在共翻译导入内质网（ER）后开始其细胞内旅程。酪氨酸酶是关键的黑素生成酶，其生物合成输出似乎受内质网（分泌途径的“入口港”）的质量控制事件调节。在内质网中成熟并通过高尔基体后，这些蛋白质在反式高尔基体网络中进行分选，以便在细胞内保留并沿内体/溶酶体途径运输，这需要细胞质暴露的信号。大多数黑素小体蛋白的细胞质尾巴中存在的双亮氨酸基序及其与衔接蛋白（AP）复合物，特别是AP-3的相互作用，对这些事件至关重要。分选信号以及与这些信号相互作用的胞质成分的缺陷会导致多种小鼠毛色表型，并引起人类色素沉着障碍。因此，产生缺乏黑素小体分选信号的截短酪氨酸酶的错义或移码突变似乎是小鼠铂色毛色表型和一部分人类眼皮肤白化病1型的原因；AP-3中的突变似乎是小鼠褐咖啡表型和人类Hermansky-Pudlak样综合征的原因。内体分选和将蛋白质靶向黑素小体似乎需要AP-3下游的其他信号和分选步骤。将黑素小体蛋白从内体/溶酶体中隔离出来的信号和机制尚不清楚。介导此类过程的潜在候选者包括由lyst和pallid基因编码的蛋白质。许多储存池疾病中黑素小体异常的常见发生表明，黑素细胞利用其他蛋白质和细胞类型共有的信号、途径和机制来组装多种特殊蛋白质并产生独特的细胞类型特异性细胞器。
