Reactome | RAB geranylgeranylation

RAB geranylgeranylation

Stable Identifier

R-HSA-8873719

DOI

10.3180/R-HSA-8873719.1

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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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
23898197	Membrane extraction of Rab proteins by GDP dissociation inhibitor characterized using attenuated total reflection infrared spectroscopy Gavriljuk, K, Itzen, A, Goody, RS, Gerwert, K, Kötting, C	Proc. Natl. Acad. Sci. U.S.A.	2013
8662963	Nucleotide dependence of Rab geranylgeranylation. Rab escort protein interacts preferentially with GDP-bound Rab Seabra, MC	J. Biol. Chem.	1996
19603039	Rab GTPases as coordinators of vesicle traffic Stenmark, H	Nat. Rev. Mol. Cell Biol.	2009
16855591	TBC-domain GAPs for Rab GTPases accelerate GTP hydrolysis by a dual-finger mechanism Pan, X, Eathiraj, S, Munson, M, Lambright, DG	Nature	2006
22694141	Structure, regulation and cellular functions of Rab geranylgeranyl transferase and its cellular partner Rab Escort Protein Gutkowska, M, Swiezewska, E	Mol. Membr. Biol.	2012
22251903	Illuminating the functional and structural repertoire of human TBC/RABGAPs Frasa, MA, Koessmeier, KT, Ahmadian, MR, Braga, VM	Nat. Rev. Mol. Cell Biol.	2012
20937701	Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors Yoshimura, S, Gerondopoulos, A, Linford, A, Rigden, DJ, Barr, FA	J. Cell Biol.	2010
20512138	Membrane targeting mechanism of Rab GTPases elucidated by semisynthetic protein probes Wu, YW, Oesterlin, LK, Tan, KT, Waldmann, H, Alexandrov, K, Goody, RS	Nat. Chem. Biol.	2010
25402849	Protein prenylation: enzymes, therapeutics, and biotechnology applications Palsuledesai, CC, Distefano, MD	ACS Chem. Biol.	2015
7991565	Rab geranylgeranyl transferase catalyzes the geranylgeranylation of adjacent cysteines in the small GTPases Rab1A, Rab3A, and Rab5A Farnsworth, CC, Seabra, MC, Ericsson, LH, Gelb, MH, Glomset, JA	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 Shen, F, Seabra, MC	J. Biol. Chem.	1996
8164745	Membrane targeting of the small GTPase Rab9 is accompanied by nucleotide exchange Soldati, T, Shapiro, AD, Svejstrup, AB, Pfeffer, SR	Nature	1994
7957092	Rab escort protein-1 is a multifunctional protein that accompanies newly prenylated rab proteins to their target membranes Alexandrov, K, Horiuchi, H, Steele-Mortimer, O, Seabra, MC, Zerial, M	EMBO J.	1994
1944536	Hypervariable C-terminal domain of rab proteins acts as a targeting signal Chavrier, P, Gorvel, JP, Stelzer, E, Simons, K, Gruenberg, J, Zerial, M	Nature	1991
22065758	Insights regarding guanine nucleotide exchange from the structure of a DENN-domain protein complexed with its Rab GTPase substrate Wu, X, Bradley, MJ, Cai, Y, Kümmel, D, De La Cruz, EM, Barr, FA, Reinisch, KM	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 Baron, RA, Seabra, MC	Biochem. J.	2008
8349690	Rab GDP dissociation inhibitor as a general regulator for the membrane association of rab proteins Ullrich, O, Stenmark, H, Alexandrov, K, Huber, LA, Kaibuchi, K, Sasaki, T, Takai, Y, Zerial, M	J. Biol. Chem.	1993
14574414	Yip3 catalyses the dissociation of endosomal Rab-GDI complexes Sivars, U, Aivazian, D, Pfeffer, SR	Nature	2003
25341920	Rab proteins and the compartmentalization of the endosomal system Wandinger-Ness, A, Zerial, M	Cold Spring Harb Perspect Biol	2014