5noi | pdb_00005noi
human Robo2 extracellular domains 4-5
Structural highlights
DiseaseROBO2_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. FunctionROBO2_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 PubMedRobo receptors play pivotal roles in axonal guidance as well as in neurogenesis, angiogenesis, cell migration, and cancer progression and invasiveness. They are considered to be attractive drug targets for the treatment of cancer, ocular neovascular disorders, chronic kidney diseases, and more. Despite their great importance, the mechanisms by which Robo receptors switch from their "off" to "on" states remain obscure. One possibility involves a monomer-to-dimer or dimer-to-monomer transition that facilitates the recruitment and activation of enzymatic effectors to instigate intracellular signaling. However, it is not known which domains mediate Robo dimerization, or the structural properties of the dimeric interactions. Here, we identify the extracellular Ig4 (D4) as a Robo dimerization domain. We have determined the crystal structure of the tandem Ig4-5 domains (D4-5) of human Robo2 and found that a hydrophobic surface on D4 mediates close homotypic contacts with a reciprocal D4. Analytical ultracentrifugation measurements of intact and mutated D4-5 shows that dimerization through the D4 interface is specific and has a dimerization dissociation constant of 16.9muM in solution. Direct fluorescence resonance energy transfer dimerization measurements in HEK293 cells corroborate the dimerization of transmembrane hRobo2 through D4, and a functional COS-7 cell collapse assay links D4-mediated dimerization with Robo intracellular signaling. The high level of conservation in the D4 dimerization interface throughout all Robo orthologs and paralogs implies that D4-mediated dimerization is a central hallmark in Robo activation and signaling. Robo Ig4 Is a Dimerization Domain.,Yom-Tov G, Barak R, Matalon O, Barda-Saad M, Guez-Haddad J, Opatowsky Y J Mol Biol. 2017 Oct 7. pii: S0022-2836(17)30472-2. doi:, 10.1016/j.jmb.2017.10.002. PMID:29017837[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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