All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding
All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding
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DOI：
10.1016/j.bbrc.2008.02.067
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发表时间：
2008-05-02
影响因子：
3.1
通讯作者：
De Camilli, Pietro
中科院分区：
文献类型：
--
作者：
McCrea, Heather J.;Paradise, Summer;De Camilli, Pietro
肌醇 5-磷酸酶 OCRL 的突变导致 Lowe 综合征（一种以双侧白内障、智力迟钝、新生儿肌张力低下和肾范可尼综合征为特征的 X 连锁疾病）和 Dent 病（另一种以肾脏重吸收缺陷为特征的 X 连锁疾病）。我们之前描述了 OCRL 与内吞接头 APPL1 的相互作用，APPL1 将 OCRL 与涉及疾病表型的蛋白质网络连接起来。在这里，我们提供了新的证据，表明在将 OCRL 靶向内吞途径膜的相互作用中，与 APPL1 的结合是唯一一种被该蛋白 ASH-RhoGAP 结构域中所有已知致病错义突变所消除的相互作用。此外，我们证明 APPL1 和 rab5 独立地有助于招募 OCRL 至由组成型活性 Rab5 表达诱导的扩大的内体。因此，与 APPL1 的结合有助于将 OCRL 定位在特定的细胞位点，这种相互作用的破坏可能在疾病中发挥作用。 (C) 2008 Elsevier Inc. 保留所有权利。
Mutations in the inositol 5-phosphatase OCRL are responsible for Lowe syndrome, an X-linked disorder characterized by bilateral cataracts, mental retardation, neonatal hypotonia, and renal Fanconi syndrome, and for Dent disease, another X-linked condition characterized by kidney reabsorption defects. We have previously described an interaction of OCRL with the endocytic adaptor APPL1 that links OCRL to protein networks involved in the disease phenotype. Here, we provide new evidence showing that among the interactions which target OCRL to membranes of the endocytic pathway, binding to APPL1 is the only one abolished by all known disease-causing missense mutations in the ASH-RhoGAP domains of the protein. Furthermore, we demonstrate that APPL1 and rab5 independently contribute to recruit OCRL to enlarged endosomes induced by the expression of constitutively active Rab5. Thus, binding to APPL1 helps localize OCRL at specific cellular sites, and disruption of this interaction may play a role in disease. (C) 2008 Elsevier Inc. All rights reserved.