All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding
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- 作者：Heather J. McCrea ; Summer Paradise ; Livia Tomasini ; Maria Addis ; Maria Antonietta Melis ; Maria Antonietta De Matteis ; Pietro De Camilli
- 关键词：OCRL ; Lowe Syndrome ; APPL1 ; Rab5 ; Endosome ; Oculocerebrorenal Syndrome of Lowe
- 刊名：Biochemical and Biophysical Research Communications
- 出版年：2008
- 出版时间：2 May 2008
- 年：2008
- 卷：369
- 期：2
- 页码：493-499
- 全文大小：1994 K
文摘
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.