Tuning the Cellular Trafficking of the Lysosomal Peptide Transporter TAPL by its N-terminal Domain
Tuning the Cellular Trafficking of the Lysosomal Peptide Transporter TAPL by its N-terminal Domain
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DOI：
10.1111/j.1600-0854.2009.01021.x
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发表时间：
2010-03-01
期刊：
影响因子：
4.5
通讯作者：
Abele, Rupert
中科院分区：
文献类型：
--
作者：
Demirel, Oezlem;Bangert, Irina;Abele, Rupert
同二聚体 ATP 结合盒 (ABC) 转运复合物 TAPL（与抗原加工相关的转运蛋白，ABCB9）将多种肽从胞质溶胶转运到溶酶体的内腔中。与已知蛋白质缺乏任何序列同源性的额外 N 端跨膜结构域 (TMD0) 的存在将 TAPL 与其亚家族的大多数其他 ABC 转运蛋白区分开来。通过剖析 TAPL，我们可以为核心复合体和 TMD0 分配不同的功能。核心-TAPL 复合物由六个预测的跨膜螺旋和一个核苷酸结合域组成，足以进行肽转运，表明核心转运复合物正确靶向并组装在膜中。引人注目的是，与全长转运蛋白相比，核心易位复合物优先靶向质膜。然而，单独的TMD0（包含假定的四跨膜螺旋束）运输至溶酶体。共表达后，TMD0 与核心易位机制形成稳定的非共价连接复合物，并引导核心-TAPL 进入溶酶体区室。因此，TMD0 代表一个独特的结构域，它独立折叠并编码溶酶体靶向信息。这些结果在 TAPL 的运输、折叠和功能方面进行了讨论。
The homodimeric ATP-binding cassette (ABC) transport complex TAPL (transporter associated with antigen processing-like, ABCB9) translocates a broad spectrum of peptides from the cytosol into the lumen of lysosomes. The presence of an extra N-terminal transmembrane domain (TMD0) lacking any sequence homology to known proteins distinguishes TAPL from most other ABC transporters of its subfamily. By dissecting TAPL, we could assign distinct functions to the core complex and TMD0. The core-TAPL complex, composed of six predicted transmembrane helices and a nucleotide-binding domain, is sufficient for peptide transport, showing that the core transport complex is correctly targeted to and assembled in the membrane. Strikingly, in contrast to the full-length transporter, the core translocation complex is targeted preferentially to the plasma membrane. However, TMD0 alone, comprising a putative four transmembrane helix bundle, traffics to lysosomes. Upon coexpression, TMD0 forms a stable non-covalently linked complex with the core translocation machinery and guides core-TAPL into lysosomal compartments. Therefore, TMD0 represents a unique domain, which folds independently and encodes the information for lysosomal targeting. These outcomes are discussed in respect of trafficking, folding and function of TAPL.