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Molecular basis for Rab prenylation.

Rab escort proteins (REP) 1 and 2 are closely related mammalian proteins required for prenylation of newly synthesized Rab GTPases by the cytosolic heterodimeric Rab geranylgeranyl transferase II complex (RabGG transferase). REP1 in mammalian cells is the product of the choroideremia gene (CHM). CHM/REP1 deficiency in inherited disease leads to degeneration of retinal pigmented epithelium and loss of vision. We now show that amino acid residues required for Rab recognition are critical for function of the yeast REP homologue Mrs6p, an essential protein that shows 50% homology to mammalian REPs. Mutant Mrs6p unable to bind Rabs failed to complement growth of a mrs6Delta null strain and were found to be dominant inhibitors of growth in a wild-type MRS6 strain. Mutants were identified that did not affect Rab binding, yet prevented prenylation in vitro and failed to support growth of the mrs6Delta null strain. These results suggest that in the absence of Rab binding, REP interaction with RabGG transferase is maintained through Rab-independent binding sites, providing a molecular explanation for the kinetic properties of Rab prenylation in vitro. Analysis of the effects of thermoreversible temperature-sensitive (mrs6(ts)) mutants on vesicular traffic in vivo showed prenylation activity is only transiently required to maintain normal growth, a result promising for therapeutic approaches to disease.

Pubmed ID: 10893259 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Cell Division | Choroideremia | Cytoplasm | Fungal Proteins | Genetic Complementation Test | Guanine Nucleotide Dissociation Inhibitors | Intracellular Membranes | Models, Molecular | Mutagenesis | Point Mutation | Protein Binding | Protein Prenylation | Protein Structure, Tertiary | Saccharomyces cerevisiae | Saccharomyces cerevisiae Proteins | Sequence Homology, Amino Acid | Structure-Activity Relationship | Temperature | Vacuoles | rab GTP-Binding Proteins

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Cold Spring Harbor Laboratory

A non-profit, private research and education institution that performs molecular and genetic research used to generate methods for better diagnostics and treatments for cancer and neurological diseases. This lab has done specific research of cancer-causing genes and their respective signaling pathways. They have also researched mutations and structural variations of the human genome that could cause neurodevelopmental and neurodegenerative illnesses such as autism, schizophrenia, and Alzheimer's and Parkinson's diseases. This laboratory is also involved in plant genetics and quantitative biology.

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