Reactome: A Curated Pathway Database

RAB geranylgeranylation

Stable Identifier
R-HSA-8873719
Type
Pathway
Species
Homo sapiens
Locations in the PathwayBrowser
Summation

Human cells have more than 60 RAB proteins that are involved in trafficking of proteins in the endolysosomal system. These small GTPases contribute to trafficking specificity by localizing to the membranes of different endocytic compartments and interacting with effectors such as sorting adaptors, tethering factors, kinases, phosphatases and tubular-vesicular cargo (reviewed in Stenmark et al, 2009; Wandinger-Ness and Zerial, 2014). RAB localization depends on a number of factors including C-terminal prenylation, the sequence of an upstream hypervariable regions and what nucleotide is bound (Chavrier et al, 1991; Ullrich et al, 1993; Soldati et al, 1994; Farnsworth et al, 1994; Seabra, 1996; Wu et al, 2010; reviewed in Stenmark, 2009; Wandinger-Ness and Zerial, 2014). In the active, GTP-bound form, prenylated RAB proteins are membrane associated, while in the inactive GDP-bound form, RABs are extracted from the target membrane and exist in a soluble form in complex with GDP dissociation inhibitors (GDIs) (Ullrich et al, 1993; Soldati et al, 1994; Gavriljuk et al, 2103). Conversion between the inactive and active form relies on the activities of RAB guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) (Yoshimura et al, 2010; Wu et al, 2011; Pan et al, 2006; Frasa et al, 2012; reviewed in Stenmark, 2009; Wandinger-Ness and Zerial, 2014).
Newly synthesized RABs are bound by a RAB escort protein, CHM (also known as REP1) or CHML (REP2) (Alexandrov et al, 1994; Shen and Seabra, 1996). CHM/REP proteins are the substrate-binding component of the trimeric RAB geranylgeranyltransferase enzyme (GGTaseII) along with the two catalytic subunits RABGGTA and RABGGTB (reviewed in Gutkowska and Swiezewska, 2012; Palsuledesai and Distefano, 2015). REP proteins recruit the unmodified RAB in its GDP-bound state to the GGTase for sequential geranylgeranylation at one or two C-terminal cysteine residues (Alexandrov et al, 1994; Seabra et al 1996; Shen and Seabra, 1996; Baron and Seabra, 2008). After geranylgeranylation, CHM/REP proteins remain in complex with the geranylgeranylated RAB and escort it to its target membrane, where its activity is regulated by GAPs, GEFs, GDIs and membrane-bound GDI displacement factors (GDFs) (Sivars et al, 2003; reviewed in Stenmark, 2009; Wandinger-Ness and Zerial, 2014).

Literature References
PubMed ID Title Journal Year
8662963 Nucleotide dependence of Rab geranylgeranylation. Rab escort protein interacts preferentially with GDP-bound Rab J. Biol. Chem. 1996
23898197 Membrane extraction of Rab proteins by GDP dissociation inhibitor characterized using attenuated total reflection infrared spectroscopy Proc. Natl. Acad. Sci. U.S.A. 2013
19603039 Rab GTPases as coordinators of vesicle traffic Nat. Rev. Mol. Cell Biol. 2009
16855591 TBC-domain GAPs for Rab GTPases accelerate GTP hydrolysis by a dual-finger mechanism Nature 2006
22694141 Structure, regulation and cellular functions of Rab geranylgeranyl transferase and its cellular partner Rab Escort Protein Mol. Membr. Biol. 2012
22251903 Illuminating the functional and structural repertoire of human TBC/RABGAPs Nat. Rev. Mol. Cell Biol. 2012
20937701 Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors J. Cell Biol. 2010
20512138 Membrane targeting mechanism of Rab GTPases elucidated by semisynthetic protein probes Nat. Chem. Biol. 2010
25402849 Protein prenylation: enzymes, therapeutics, and biotechnology applications ACS Chem. Biol. 2015
7991565 Rab geranylgeranyl transferase catalyzes the geranylgeranylation of adjacent cysteines in the small GTPases Rab1A, Rab3A, and Rab5A Proc. Natl. Acad. Sci. U.S.A. 1994
8631982 Mechanism of digeranylgeranylation of Rab proteins. Formation of a complex between monogeranylgeranyl-Rab and Rab escort protein J. Biol. Chem. 1996
8164745 Membrane targeting of the small GTPase Rab9 is accompanied by nucleotide exchange Nature 1994
7957092 Rab escort protein-1 is a multifunctional protein that accompanies newly prenylated rab proteins to their target membranes EMBO J. 1994
1944536 Hypervariable C-terminal domain of rab proteins acts as a targeting signal Nature 1991
22065758 Insights regarding guanine nucleotide exchange from the structure of a DENN-domain protein complexed with its Rab GTPase substrate Proc. Natl. Acad. Sci. U.S.A. 2011
18532927 Rab geranylgeranylation occurs preferentially via the pre-formed REP-RGGT complex and is regulated by geranylgeranyl pyrophosphate Biochem. J. 2008
8349690 Rab GDP dissociation inhibitor as a general regulator for the membrane association of rab proteins J. Biol. Chem. 1993
14574414 Yip3 catalyses the dissociation of endosomal Rab-GDI complexes Nature 2003
25341920 Rab proteins and the compartmentalization of the endosomal system Cold Spring Harb Perspect Biol 2014
Participants
Participant Of
Orthologous Events