6i9s
hRobo2 Extracellular Domains 2-3
Structural highlights
Disease[ROBO2_HUMAN] Defects in ROBO2 are the cause of vesicoureteral reflux type 2 (VUR2) [MIM:610878]. VUR is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter and is associated with reflux nephropathy, the cause of 15% of end-stage renal disease in children and young adults.[1] Note=A chromosomal aberration involving ROBO2 is a cause of multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. Translocation t(Y;3)(p11;p12) with PCDH11Y. This translocation disrupts ROBO2 and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro. Function[ROBO2_HUMAN] Receptor for SLIT2, and probably SLIT1, which are thought to act as molecular guidance cue in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuronal development. Publication Abstract from PubMedProper brain function requires high-precision neuronal expansion and wiring, processes controlled by the transmembrane Roundabout (Robo) receptor family and their Slit ligands. Despite their great importance, the molecular mechanism by which Robos' switch from "off" to "on" states remains unclear. Here, we report a 3.6 A crystal structure of the intact human Robo2 ectodomain (domains D1-8). We demonstrate that Robo cis dimerization via D4 is conserved through hRobo1, 2, and 3 and the C. elegans homolog SAX-3 and is essential for SAX-3 function in vivo. The structure reveals two levels of auto-inhibition that prevent premature activation: (1) cis blocking of the D4 dimerization interface and (2) trans interactions between opposing Robo receptors that fasten the D4-blocked conformation. Complementary experiments in mouse primary neurons and C. elegans support the auto-inhibition model. These results suggest that Slit stimulation primarily drives the release of Robo auto-inhibition required for dimerization and activation. Structural Principles in Robo Activation and Auto-inhibition.,Barak R, Yom-Tov G, Guez-Haddad J, Gasri-Plotnitsky L, Maimon R, Cohen-Berkman M, McCarthy AA, Perlson E, Henis-Korenblit S, Isupov MN, Opatowsky Y Cell. 2019 Mar 4. pii: S0092-8674(19)30153-9. doi: 10.1016/j.cell.2019.02.004. PMID:30853216[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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