Rab interacting lysosomal protein (RILP) contains a domain which contains two coiled-coil regions and is found mainly in the cytosol. RILP is recruited onto late endosomal and lysosomal membranes by Rab7 and acts as a downstream effector of Rab7 []. This recruitment process is important for phagosome maturation and fusion with late endosomes and lysosomes.
RMC1 is a componement of the the CCZ1-MON1 complex, which functions as a guanine exchange factor (GEF) for RAB7 during endocytic and autophagic flux to the lysosome. It positively regulates CCZ1-MON1 function that is necessary for endosomal/autophagic flux and efficient RAB7 localization on CD63-positive vesicle membranes [].
Members of this family have been called SAND proteins []although these proteins do not contain a SAND domain. In Saccharomyces cerevisiae, Mon1 is part of the Mon1-Ccz1 complex that acts as the guanine nucleotide exchange factor (GEF) of the yeast Rab7 GTPase Ypt7 [, ]. The Mon1/Ccz1 complex is conserved in eukaryotic evolution and members of this family (previously known as DUF254) are distant homologues to domains of known structure that assemble into cargo vesicle adapter (AP) complexes [, ].
Phafin1 (also known as PLEKHF1 or LAPF) recruits phosphorylated p53 to lysosomes and triggers caspase-independent apoptosis. It is also is involved in lysosomal sorting and induction of autophagosome formation via Rab7 signaling []. Phafin2 (also called EAPF, FLJ13187, ZFYVE18 or PLEKHF2) is differentially expressed in the liver cancer cell and regulates the structure and function of the endosomes through Rab5-dependent processes []. Phafin2 modulates the cell's response to extracellular stimulation by modulating the receptor density on the cell surface [].Phafin1 and Phafin2 are composed of both PH and FYVE domains. Phafin1 has an additional C-terminal tail domain. Phafin1, but not phafin2, exhibits significant binding to PI(4)P and PI(5)P []. This entry represents the PH domain of phafin 1 and 2.
This is the Rubicon homology domain (RH) characterised at the C-terminal of Rubicon, PLEKHM1 and Pacer, proteins that modulate late steps in autophagy [, ]. Rubicon (RUBCN) negatively regulates autophagy and endolysosomal trafficking by inhibiting PI3K complex II (PI3KC3-C2), which impairs autophagosome maturation process. Decrease in autophagy is associated to aging, then suppression of this process by Rubicon has been linked to decreased clearance of alpha-synuclein aggregates in neural tissues, impairment of liver cell homeostasis, and interstitial fibrosis in the kidney. PLEKHM1 is an adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways [, ], being involved in the suppression of endocytic transport rather than autophagosome maturation. Mutations in PLEKHM1 causes osteopetrosis []. On the other hand, Pacer (Protein associated with UVRAG as autophagy enhancer or Rubicon-like) positively regulates autophagy, promoting autophagosome maturation by facilitating the biogenesis of phosphatidylinositol 3-phosphate (PtdIns3P) in late steps of autophagy [, ]. It antagonizes RUBCN, thereby stimulating phosphatidylinositol 3-kinase activity of the PI3K/PI3KC3 complex []. Pacer is involved in neuronal autophagy, whose deficiency leads to impaired autophagy and accumulation of protein aggregates in ALS which correlates with cell death and vulnerability of motoneurons during ALS pathogenesis [].This domain contains nine conserved cysteines and one conserved histidine, which have been predicted to bind divalent zinc cations, being required for Rubicon and PLEKHM1 to interact with Rab7 [, ].
