Structure of the Rab7:REP-1 complex: insights into the mechanism of Rab prenylation and choroideremia disease

Alexey Rak; Olena Pylypenko; Anca Niculae; Konstantin Pyatkov; Roger S Goody; Kirill Alexandrov

doi:10.1016/j.cell.2004.05.017

Structure of the Rab7:REP-1 complex: insights into the mechanism of Rab prenylation and choroideremia disease

Cell. 2004 Jun 11;117(6):749-60. doi: 10.1016/j.cell.2004.05.017.

Authors

Alexey Rak¹, Olena Pylypenko, Anca Niculae, Konstantin Pyatkov, Roger S Goody, Kirill Alexandrov

Affiliation

¹ Max-Planck-Institute for Molecular Physiology, Otto-Hahn-Str. 11, 44227 Dortmund, Germany.

PMID: 15186776
DOI: 10.1016/j.cell.2004.05.017

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Alkyl and Aryl Transferases / chemistry
Alkyl and Aryl Transferases / genetics
Alkyl and Aryl Transferases / metabolism*
Binding Sites / physiology
Carrier Proteins / metabolism
Catalytic Domain / physiology
Choroideremia / genetics
Choroideremia / metabolism*
Humans
Macromolecular Substances
Models, Molecular
Molecular Structure
Protein Binding / physiology
Protein Prenylation / physiology*
Protein Structure, Tertiary / physiology
Terpenes / metabolism*
rab GTP-Binding Proteins / chemistry
rab GTP-Binding Proteins / genetics
rab GTP-Binding Proteins / metabolism*
rab27 GTP-Binding Proteins
rab7 GTP-Binding Proteins

Substances

Adaptor Proteins, Signal Transducing
CHM protein, human
CHML protein, human
Carrier Proteins
Macromolecular Substances
Terpenes
rab27 GTP-Binding Proteins
rab7 GTP-Binding Proteins
rab7 GTP-binding proteins, human
Alkyl and Aryl Transferases
RAB27A protein, human
rab GTP-Binding Proteins

Associated data

PDB/1VG9
PDB/IVG0
PDB/IVG1
PDB/IVG8