Abstract
Simple SummaryThe RLIP76 protein is present at high levels in multiple cancers, compared with levels in normal cells. In cancer cells it is thought to be important for removal of chemotherapeutics, while in normal cells it has been implicated in endocytosis, stress response and mitochondrial fission. Although RLIP76 is a potential target for ovary, breast, lung, colon, prostate and kidney cancers, only the middle third of the protein has been structurally characterized. Understanding the full structure of RLIP76 will help us to better understand the signalling pathways in which it is involved and by extension its role in cancer.RLIP76/RalBP1 is an ATP-dependent transporter of glutathione conjugates, which is overexpressed in various human cancers, but its diverse functions in normal cells, which include endocytosis, stress response and mitochondrial dynamics, are still not fully understood. The protein can be divided into three distinct regions, each with its own structural properties. At the centre of the protein are two well-defined domains, a GTPase activating protein domain targeting Rho family small G proteins and a small coiled-coil that binds to the Ras family small GTPases RalA and RalB. In engaging with Rho and Ral proteins, RLIP76 bridges these two distinct G protein families. The N-terminal region is predicted to be disordered and is rich in basic amino acids, which may mediate membrane association, consistent with its role in transport. RLIP76 is an ATP-dependent transporter with ATP-binding sites within the N-terminus and the Ral binding domain. Furthermore, RLIP76 is subject to extensive phosphorylation, particularly in the N-terminal region. In contrast, the C-terminal region is thought to form an extensive coiled-coil that could mediate dimerization. Here, we review the structural features of RLIP76, including experimental data and computational predictions, and discuss the implications of its various post-translational modifications.
Highlights
RLIP76, known as RalBP1, is a 76 kDa protein that was simultaneously discovered by three groups as a downstream effector of the Ral family of small GTPases
The overall fold and position of the arginine finger in RLIP76 and p50RhoGAP are similar but the RLIP76 RhoGAP domain binds to Cdc42 and Rac1 with affinities at least 100-fold lower
Increased GTPase activating protein (GAP) activity in vitro has been observed for GAPs when either the GAP or GTPase is tethered to a membrane [37,38], so it is possible that RLIP76 has one or more membrane-localization motifs that could explain the higher GAP activity observed in vivo
Summary
RLIP76, known as RalBP1, is a 76 kDa protein that was simultaneously discovered by three groups as a downstream effector of the Ral family of small GTPases. The N-terminal third of RLIP76 (residues 1–190) binds to several other proteins It interacts with the interdomain linker of the mu subunit of the clathrin adapter complex, AP2, leading to receptor mediated endocytosis of EGFR [14]. Residues 1–392 of RLIP76, which includes the N-terminus and the RhoGAP domain, interact with the small GTPase R-Ras, leading to ARNO and subsequently Arf activation. As with CDK1 and Epsin, RLIP76 acts as a scaffold and by forming a complex with both Cyclin B-CDK1 and Drp, it facilitates phosphorylation of Drp by CDK1, leading to inhibition of mitochondrial fission. The RLIP76 C-terminus interacts with the postsynaptic scaffold protein PSD-95, leading to endocytosis of PSD-95 associated receptors in synapses. Phosphorylation of rat RLIP76 at Thr645 (Thr653 in human RLIP76) inhibits PSD-95 binding [27]
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