Cremers F P, Armstrong S A, Seabra M C, Brown M S, Goldstein J L
Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Texas 75235-9046.
J Biol Chem. 1994 Jan 21;269(3):2111-7.
Rab escort proteins (REPs) bind to newly synthesized Rab proteins and remain bound during and after the attachment of a geranylgeranyl (GG) group by the catalytic component of the Rab GG transferase. Transfer of the GG group is absolutely dependent on the participation of a REP. REP-1, the first characterized REP, is produced by a gene on the X chromosome that is defective in patients with choroideremia, a form of retinal degeneration. Cremers et al. (Cremers, F.P.M., Molloy, C. M., van de Pol, D. J. R., van den Hurk, J. A. J. M., Bach, I., Geurts van Kessel, A. H. M., and Ropers, H.-H. (1992) Hum. Mol. Genet. 1, 71-75) isolated a related gene, designated choroideremia-like, which encodes a protein that closely resembles REP-1. In the current studies, we produced REP-1 and REP-2 by recombinant DNA methods and showed that both proteins were approximately equal in facilitating the attachment of GG groups to several Rab proteins, including Rab1A, Rab5A, and Rab6. However, REP-2 was only 25% as active as REP-1 in supporting GG attachment to Rab3A and Rab3D. The low activity toward Rab3A was increased to that of Rab1A when the COOH-terminal 12 amino acids of Rab3A were replaced with the corresponding residues of Rab1A. We suggest that REP-2 substitutes for the absent function of REP-1 in nonretinal cells of patients with choroideremia, thus preventing cellular dysfunction throughout the body. In the retina, REP-2 may be only partially effective, leading eventually to retinal degeneration and blindness.
Rab护送蛋白（REPs）与新合成的Rab蛋白结合，并在Rab香叶基香叶基（GG）转移酶的催化成分将GG基团连接期间及之后一直保持结合状态。GG基团的转移绝对依赖于REP的参与。REP-1是首个被鉴定的REP，由X染色体上的一个基因产生，患有视网膜色素变性（脉络膜血症）的患者该基因存在缺陷。克雷默斯等人（Cremers, F.P.M., Molloy, C. M., van de Pol, D. J. R., van den Hurk, J. A. J. M., Bach, I., Geurts van Kessel, A. H. M., and Ropers, H.-H. (1992) Hum. Mol. Genet. 1, 71 - 75）分离出一个相关基因，命名为类脉络膜血症基因，它编码一种与REP-1极为相似的蛋白质。在当前研究中，我们通过重组DNA方法制备了REP-1和REP-2，并表明这两种蛋白质在促进GG基团与几种Rab蛋白（包括Rab1A、Rab5A和Rab6）的连接方面大致相当。然而，在支持GG基团与Rab3A和Rab3D的连接方面，REP-2的活性仅为REP-1的25%。当Rab3A的COOH末端12个氨基酸被Rab1A的相应残基取代时，其对Rab3A的低活性提高到了Rab1A的水平。我们认为，REP-2替代了脉络膜血症患者非视网膜细胞中缺失的REP-1功能，从而防止全身细胞功能障碍。在视网膜中，REP-2可能仅部分有效，最终导致视网膜变性和失明。
