@article{HankeGogokhiaFrederickZhangetal.2018,
  author    = {Hanke-Gogokhia, Christin and Frederick, Jeanne M. and Zhang, Houbin and Baehr, Wolfgang},
  title     = {Binary Function of ARL3-GTP Revealed by Gene Knockouts},
  series = {Retinal Degenerative Diseases : Mechanisms and Experimental Therapy},
  volume    = {1074},
  journal   = {Retinal Degenerative Diseases : Mechanisms and Experimental Therapy},
  publisher = {Springer},
  address   = {Cham},
  isbn      = {978-3-319-75402-4},
  issn      = {0065-2598},
  doi       = {10.1007/978-3-319-75402-4_39},
  pages     = {317 -- 325},
  year      = {2018},
  abstract  = {UNC119 and PDE delta are lipid-binding proteins and are thought to form diffusible complexes with transducin-alpha and prenylated OS proteins, respectively, to mediate their trafficking to photoreceptor outer segments. Here, we investigate mechanisms of trafficking which are controlled by Arf-like protein 3 (Arl3), a small GTPase. The activity of ARL3 is regulated by a GEF (ARL13b) and a GAP (RP2). In a mouse germline knockout of RP2, ARL3-GTP is abundant as its intrinsic GTPase activity is extremely low. High levels of ARL3-GTP impair binding and trafficking of cargo to the outer segment. Germline knockout of ARL3 is embryonically lethal generating a syndromic ciliopathy-like phenotype. Retina-and rod-specific knockout of ARL3 allow to determine the precise mechanisms leading to photoreceptor degeneration. The knockouts reveal binary functions of ARL3-GTP as a key molecule in late-stage photoreceptor ciliogenesis and cargo displacement factor.},
  language  = {en}
}
@article{ZhangHankeGogokhiaJiangetal.2015,
  author    = {Zhang, Houbin and Hanke-Gogokhia, Christin and Jiang, Li and Li, Xiaobo and Wang, Pu and Gerstner, Cecilia D. and Frederick, Jeanne M. and Yang, Zhenglin and Baehr, Wolfgang},
  title     = {Mistrafficking of prenylated proteins causes retinitis pigmentosa 2},
  series = {The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology},
  volume    = {29},
  journal   = {The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology},
  number    = {3},
  publisher = {Federation of American Societies for Experimental Biology},
  address   = {Bethesda},
  issn      = {0892-6638},
  doi       = {10.1096/fj.14-257915},
  pages     = {932 -- 942},
  year      = {2015},
  abstract  = {The retinitis pigmentosa 2 polypeptide (RP2) functions as a GTPase-activating protein (GAP) for ARL3 (Arf-like protein 3), a small GTPase. ARL3 is an effector of phosphodiesterase 6 Delta (PDE6D), a prenyl-binding protein and chaperone of prenylated protein in photoreceptors. Mutations in the human RP2 gene cause X-linked retinitis pigmentosa (XLRP) and cone-rod dystrophy (XL-CORD). To study mechanisms causing XLRP, we generated an RP2 knockout mouse. The RP2h(-/-) mice exhibited a slowly progressing rod-cone dystrophy simulating the human disease. RP2h(-/-) scotopic a-wave and photopic b-wave amplitudes declined at 1 mo of age and continued to decline over the next 6 mo. Prenylated PDE6 subunits and G-protein coupled receptor kinase 1 (GRK1) were unable to traffic effectively to the RP2h(-/-) outer segments. Mechanistically, absence of RP2 GAP activity increases ARL3-GTP levels, forcing PDE6D to assume a predominantly "closed" conformation that impedes binding of lipids. Lack of interaction disrupts trafficking of PDE6 and GRK1 to their destination, the photoreceptor outer segments. We propose that hyperactivity of ARL3-GTP in RP2 knockout mice and human patients with RP2 null alleles leads to XLRP resembling recessive rod-cone dystrophy.},
  language  = {en}
}