Structure, exchange determinants, and family-wide rab specificity of the tandem helical bundle and Vps9 domains of Rabex-5

Cell. 2004 Sep 3;118(5):607-17. doi: 10.1016/j.cell.2004.08.009.


The Rab5 GTPase, an essential regulator of endocytosis and endosome biogenesis, is activated by guanine-nucleotide exchange factors (GEFs) that contain a Vps9 domain. Here, we show that the catalytic core of the Rab GEF Rabex-5 has a tandem architecture consisting of a Vps9 domain stabilized by an indispensable helical bundle. A family-wide analysis of Rab specificity demonstrates high selectivity for Rab5 subfamily GTPases. Conserved exchange determinants map to a common surface of the Vps9 domain, which recognizes invariant aromatic residues in the switch regions of Rab GTPases and selects for the Rab5 subfamily by requiring a small nonacidic residue preceding a critical phenylalanine in the switch I region. These and other observations reveal unexpected similarity with the Arf exchange site in the Sec7 domain.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence / physiology
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Catalytic Domain / physiology
  • Endocytosis / physiology*
  • Guanine Nucleotide Exchange Factors / chemistry*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation / genetics
  • Phenylalanine / chemistry
  • Protein Binding / physiology*
  • Protein Structure, Secondary / physiology
  • Sequence Homology, Amino Acid
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism
  • rab5 GTP-Binding Proteins / metabolism*


  • ALS2 protein, human
  • Carrier Proteins
  • Guanine Nucleotide Exchange Factors
  • Intracellular Signaling Peptides and Proteins
  • RABGEF1 protein, human
  • RIN1 protein, human
  • Phenylalanine
  • rab GTP-Binding Proteins
  • rab5 GTP-Binding Proteins

Associated data

  • PDB/1TXU