Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1

Abstract

Mutations of the inositol 5′ phosphatase oculocerebrorenal syndrome of Lowe (OCRL) give rise to the congenital X-linked disorders oculocerebrorenal syndrome of Lowe and Dent disease, two conditions giving rise to abnormal kidney proximal tubule reabsorption, and additional nervous system and ocular defects in the case of Lowe syndrome. Here, we identify two closely related endocytic proteins, Ses1 and Ses2, which interact with the ASH-RhoGAP-like (ASPM-SPD-2-Hydin homology and Rho-GTPase Activating Domain-like) domain of OCRL. The interaction is mediated by a short amino acid motif similar to that used by the rab-5 effector APPL1 (Adaptor Protein containing pleckstrin homology [PH] domain, PTB domain and Leucine zipper motif 1) APPL1 for OCRL binding. Ses binding is mutually exclusive with APPL1 binding, and is disrupted by the same missense mutations in the ASHRhoGAP-like domain that also disrupt APPL1 binding. Like APPL1, Ses1 and -2 are localized on endosomes but reside on different endosomal subpopulations. These findings define a consensus motif (which we have called a phenylalanine and histidine [F&H] motif) for OCRL binding and are consistent with a scenario in which Lowe syndrome and Dent disease result from perturbations at multiple sites within the endocytic pathway.Dent disease | endocytosis | Lowe syndrome I nositol phospholipids play a critical regulatory function in cell physiology, including membrane traffic. The interconversion of different phosphoinositide species via the action of kinases and phosphatases plays a key role in the maturation and progression of membranes through different stations of the exocytic and endocytic pathways, coordinating these processes with signaling reactions. Thus, the correct spatial and temporal regulation of these enzymes is of central importance (1, 2). As a consequence, not only the lack of these enzymes but also the disruption of their interactions can have profound effects on cell function and result in pathological conditions (2-9).Two human diseases are caused by mutations in an enzyme that selectively dephosphorylates the inositol ring at the 5′ position, using phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ], two phosphoinositides concentrated in the plasma membrane, as its preferred substrates (10). One such disease is oculocerebrorenal syndrome of Lowe (hence the enzyme name "OCRL") (3, 11). This condition, also referred to as "Lowe syndrome," is a severe X-linked disorder characterized by congenital cataracts (12), kidney readsorption defects caused by proximal tubule dysfunction, cognitive impairment, muscle hypotonia, and autism spectrum behavioral disorders (13,14). The other condition is Dent disease, an X-linked disorder involving kidney defects very similar to those associated with Lowe syndrome but, for reasons not yet known, few other dysfunctions (15)(16)(17)(18)(19).OCRL comprises an N-terminal Pleckstrin Homology (PH) domain followed in sequence by a central inositol 5′-phospha...

SNX15 links clathrin endocytosis to the PtdIns(3)P early endosome independent of the APPL1 endosome

“…Linking this compartment to late stages of clathrin-coated pits and newly formed clathrin-coated vesicles is OCRL (oculocerebrorenal syndrome of Lowe), an APPL1-and clathrin-binding inositol 5-phosphatase (Choudhury et al, 2005;Erdmann et al, 2007;Mao et al, 2009). A further OCRL-binding protein, Ses1/2 (also known as IPIP27A/B), associates with the OCRL compartment but because of mutually exclusive binding defines an endocytic sub-population downstream of the APPL1 station (Swan et al, 2010;Noakes et al, 2011). These distinct sub-populations are therefore considered to represent stages along a common maturation pathway that links newly formed endocytic vesicles with the PtdIns3P-enriched early endosome (Huotari and Helenius, 2011).…”

Role of Ocrl1 and Inpp5E in primary cilia assembly and maintenance: a phosphatidylinositol phosphatase relay system?

“…30 It has been shown that these proteins recognize the same binding site in Ocrl1. 42 Interestingly, experimental evidence indicates that Ocrl1 first binds APPL1 on Rab5-positive endosomes to then transition to IPIP27/Ses-containing complexes on a different endosomal compartment ( Figure 3A). 42 This Ocrl1-binding relay event suggests a maturation of the Ocrl1-containing endosomal compartment.…”

“…[41][42][43] The ASH domain also constitutes a binding site for Rabs, with the highest affinity for Rab8a, [44][45][46] leading to an interaction that is critical for Ocrl1 role in ciliogenesis. 30,31,47 The RhoGAP-like domain does not exhibit GTPase-activating protein (GAP) activity but mediates binding to the Rho GTPases Rac1 and Cdc42.…”

Integrated analysis of genome-wide genetic and epigenetic association data for identification of disease mechanisms

“…The protein encoded by HMGN4 is thought to reduce the compactness of the chromatin fiber in nucleosomes, thereby enhancing transcription from chromatin templates, 8,9 while FAM109A encodes a protein that localizes to the endosome and plays a role in endocytic trafficking. 10,11 There were four other loci, ARIH1 (ariadne homolog, ubiquitin-conjugating enzyme E2 binding protein, 1) on chromosome 15, EIF1 (eukaryotic translation Initiation factor 1) on chromosome 17, SLC1A5 (solute carrier family 1 [neutral amino acid transporter], member 5) and CA11 (carbonic anhydrase XI) on chromosome 19, were found to be modestly associated with T1D genetically and epigenetically ( Table 2). EIF1 encodes a known protein translation initiation factor, whereas the protein encoded by ARIH1 is thought to maybe also play a role in protein translation.…”