Rab (G-protein)

The Rab family of proteins ( " Ras -related in brain" ) belongs to the Ras superfamily of monomeric G proteins ( GTPases ) and is conserved in eukaryotes to a large extent. In humans, there are over 60 known Rab proteins, each having a specific subcellular localization, and play a role in the intracellular Vesikelsortierung between the different compartments. A distinction is generally an active form that is bound in the GTP and an inactive GDP- containing form.

Properties

Rabs are peripheral membrane proteins that protrude from the vesicle into the cytosol, and are fixed on a Prenylanker in the membrane. After the synthesis of a Rab protein is first bound by the Rab escort protein (REP) and the enzyme geranylgeranyltransferase presented, which provides for the prenylation of usually two C-terminal cysteine ​​residues. REP functions referred to as a type of chaperone that shields the hydrophobic part of the molecule from the cytosol and transported to the membrane.

Rab proteins undergo as usual for a so-called G- proteins GTPase cycle. The activation of Rab proteins is effected by exchange of GDP for GTP by a GTP exchange factor ( GEF, Eng. Guanine nucleotide exchange factor). The GEF ensures the release of bound GDP, so that the present in a higher concentration of cytosolic GTP can bind to the Rab protein. The binding of GTP ensures conformational changes in the designated as a switch I and switch II regions of the Rab protein, so that it can interact with effector proteins below. About the effector proteins of the vesicle transport in the cell is regulated ( between organelles and between them and the plasma membrane ) via influence on Vesikelabschnürung, movement and fusion. The effector include enzymes, proteins of the cytoskeleton as well as other proteins which are involved in membrane fusion directed. The inactivation is carried out by GTP hydrolysis, which is supported by a so- GTPase -activating protein (GAP ). In the inactive state, the Rab protein are kept solubilized by the so-called GDP- dissociation inhibitor ( GDI), which has a structural similarity to REP, extracted from the membrane and the cytosol. Coupled to the change between GTP / GDP binding a cycle of localization between cytosol and membrane is additionally coupled. The activation of the Rab protein occurs substantially at the Donormembran so active Rab proteins are membranlokalisiert. After the vesicular transport, the Rab proteins are inactivated at the Akzeptormembran and converted back into the cytosol by GDI, so that they are available for further recruitment processes for Donormembran available. In the inactive state, GDP-bound Rab proteins therefore exist predominantly in the cytosol.

More than 60 different human Rab proteins are specifically localized in the cell between and regulate specific membrane transport compartments. A selection of locations and functions shown in the following table.

The mechanism of localization of the different Rab proteins to their specific Donormembranen is not yet clearly understood. However, there are different models:

Diseases

A variant of the Griscelli syndrome is caused by a point mutation in the gene encoding Rab27a. Here, the transport of melanosomes to the cell periphery, and the secretion of lytic granules is disturbed from cytotoxic T cells.

Choroideremia is an X - linked inherited disease that can lead to degeneration of the retinal epithelium and blindness. Affected is the isoform REP REP -1, which is specifically responsible for the prenylation of the retina Rab27a.

A mutation in GDI - α, one occurring mainly in synapses of the CNS isoform may cause of X-linked mental retardation, since the recycling of Rab is limited.