Mutations in Mlph, encoding a member of the Rab effector family, cause the melanosome transport defects observed in leaden mice
Mutations in Mlph, encoding a member of the Rab effector family, cause the melanosome transport defects observed in leaden mice
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DOI：
10.1073/pnas.181336698
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发表时间：
2001-08-28
影响因子：
11.1
通讯作者：
Jenkins, NA
中科院分区：
文献类型：
--
作者：
Matesic, LE;Yip, R;Jenkins, NA
的d，灰，和在毛色突变提供了一个独特的模型系统的研究在哺乳动物中的囊泡运输。所有三个突变基因座编码的基因是所需的极化运输黑素体，黑素细胞的专门的，含有色素的细胞器，到邻近的角质形成细胞，并最终进入被毛。遗传学研究表明，这些基因在相同或重叠的途径中发挥作用，并得到生化研究的支持，这些研究表明，d编码基于肌动蛋白的黑素体转运马达MyoVa，而ash编码Rab 27 a，Rab 27 a是一种定位于黑素体的蛋白质，被假定为MyoVa受体。在这里，我们表明，在编码亲黑素（Mlph），以前未描述的蛋白质与Rab效应，如颗粒蛋白，Slp 3-a，rabphilin-3A同源。与所有这些效应子一样，Mlph具有两个Zn 2+结合CX 2CX 13，14 CX 2C基序和一个短的富含芳香族的氨基酸区域，这对Rab结合至关重要。然而，Mlph不包含在这些和其他蛋白质中发现的两个Ca 2+结合C-2结构域参与囊泡运输，这表明它代表了以前未被识别的一类Rab效应子。总的来说，我们的数据表明，Mlph是黑素体运输机制的关键组成部分，并表明Mlph可能作为Rab 27 a和MyoVa运输复合物的一部分发挥作用。
The d, ash, and In coat color mutations provide a unique model system for the study of vesicle transport in mammals. All three mutant loci encode genes that are required for the polarized transport of melanosomes, the specialized, pigment-containing organelles of melanocytes, to the neighboring keratinocytes and eventually into coat hairs. Genetic studies suggest that these genes function in the same or overlapping pathways and are supported by biochemical studies showing that d encodes an actin-based melanosome transport motor, MyoVa, whereas ash encodes Rab27a, a protein that localizes to the melanosome and is postulated to serve as the MyoVa receptor. Here we show that In encodes melanophilin (Mlph), a previously undescribed protein with homology to Rab effectors such as granuphilin, Slp3-a, and rabphilin-3A. Like all of these effectors, Mlph possesses two Zn2+-binding CX2CX13,14CX2C motifs and a short aromatic-rich amino acid region that is critical for Rab binding. However, Mlph does not contain the two Ca2+-binding C-2 domains found in these and other proteins involved in vesicle transport, suggesting that it represents a previously unrecognized class of Rab effectors. Collectively, our data show that Mlph is a critical component of the melanosome transport machinery and suggest that Mlph might function as part of a transport complex with Rab27a and MyoVa.