Structure of the Rab7:REP-1 complex: insights into the mechanism of Rab prenylation and choroideremia disease.
Members of the RabGDI/REP family serve as multifunctional regulators of the Rab family of GTP binding proteins. Mutations in members of this family, such as REP-1, lead to abnormalities, including progressive retinal degradation (choroideremia) in humans. The crystal structures of the REP-1 protein in complex with monoprenylated or C-terminally truncated Rab7 proteins revealed that Rab7 interacts with the Rab binding platform of REP-1 via an extended interface involving the Switch 1 and 2 regions. The C terminus of the REP-1 molecule functions as a mobile lid covering a conserved hydrophobic patch on the surface of REP-1 that in the complex coordinates the C terminus of Rab proteins. Using semisynthetic fluorescent Rab27A, we demonstrate that although Rab27A can be prenylated by REP-2, this reaction can be effectively inhibited by other Rab proteins, providing a possible explanation for the accumulation of unprenylated Rab27A in choroideremia.
Rak
Alexey
A
Max-Planck-Institute for Molecular Physiology, Otto-Hahn-Str. 11, 44227 Dortmund, Germany.
Pylypenko
Olena
O
Niculae
Anca
A
Pyatkov
Konstantin
K
Goody
Roger S
RS
Alexandrov
Kirill
K
D048868:Adaptor Proteins, Signal Transducing; D019883:Alkyl and Aryl Transferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D020134:Catalytic Domain / Q000502:physiology; D015794:Choroideremia / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000502:physiology; D017368:Protein Prenylation / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D013729:Terpenes / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000075745:rab27 GTP-Binding Proteins; D000090802:rab7 GTP-Binding Proteins
D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human; C085460:CHML protein, human; D002352:Carrier Proteins; D046911:Macromolecular Substances; D013729:Terpenes; D000075745:rab27 GTP-Binding Proteins; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D019883:Alkyl and Aryl Transferases; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins