Reactome | RAB GEFs exchange GTP for GDP on RABs

RAB GEFs exchange GTP for GDP on RABs

Stable Identifier

R-HSA-8876198

DOI

10.3180/R-HSA-8876198.1

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Human cells have more than 60 RAB proteins that are key regulators of intracellular membrane trafficking. These small GTPases contribute to trafficking specificity by localizing to the membranes of different organelles 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; Zhen and Stenmark, 2015).

RAB localization depends on a number of factors including C-terminal prenylation, the sequence of upstream hypervariable regions and what nucleotide is bound, as well as interaction with RAB-interacting proteins (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). More recently, the activity of RAB GEFs has also been implicated in regulating the localization of RAB proteins (Blumer et al, 2103; Schoebel et al, 2009; Cabrera and Ungermann, 2013; reviewed in Barr, 2013; Zhen and Stenmark, 2015)

In the active, GTP-bound form, 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, 2013). 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; Ishida et al, 2016).

Newly synthesized RABs are bound to 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 geranylation, CHM/REP proteins remain in complex with the geranylated RAB and escort it to its target membrane, where RAB 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).

Unlike the RAB GAPS, which (to date) all contain a shared TBC domain, RAB GEFs are structurally diverse and range from monomeric to multisubunit complexes (reviewed in Fukuda et al, 2011; Frasa et al, 2012; Cherfils and Zeghouf, 2013; Ishida et al, 2016). While many GEFs contain one of three conserved GEF domains identified to date - the DENN (differentially expressed in normal and neoplastic cell) domain, the VPS9 domain and the SEC2 domain- other GEFs lack a conserved domain (reviewed in Ishida et al, 2016). Based on sequence conservation and subunit organization, GEFs can be grouped into 6 general classes: the DENND-containing GEFs, the VPS9-containing GEFs (both monomeric), the SEC2-containing GEFs (homodimeric), heterodimeric GEF complexes such as RIC1:RGP1, the multisubunit TRAPPC GEF, and others (reviewed in Barr and Lambright, 2010; Marat et al, 2011; Ishida et al, 2016). GEFs for many RABs have still not been identified, however.

Literature References

PubMed ID	Title	Journal	Year
27246931	Multiple Types of Guanine Nucleotide Exchange Factors (GEFs) for Rab Small GTPases Oguchi, ME, Fukuda, M, Ishida, M	Cell Struct. Funct.	2016
25341920	Rab proteins and the compartmentalization of the endosomal system Wandinger-Ness, A, Zerial, M	Cold Spring Harb Perspect Biol	2014
14574414	Yip3 catalyses the dissociation of endosomal Rab-GDI complexes Pfeffer, SR, Aivazian, D, Sivars, U	Nature	2003
8349690	Rab GDP dissociation inhibitor as a general regulator for the membrane association of rab proteins Kaibuchi, K, Alexandrov, K, Takai, Y, Ullrich, O, Huber, LA, Zerial, M, Sasaki, T, Stenmark, H	J. Biol. Chem.	1993
18532927	Rab geranylgeranylation occurs preferentially via the pre-formed REP-RGGT complex and is regulated by geranylgeranyl pyrophosphate Seabra, MC, Baron, RA	Biochem. J.	2008
1944536	Hypervariable C-terminal domain of rab proteins acts as a targeting signal Gorvel, JP, Gruenberg, J, Stelzer, E, Zerial, M, Chavrier, P, Simons, K	Nature	1991
23303910	Regulation of small GTPases by GEFs, GAPs, and GDIs Zeghouf, M, Cherfils, J	Physiol. Rev.	2013
7957092	Rab escort protein-1 is a multifunctional protein that accompanies newly prenylated rab proteins to their target membranes Seabra, MC, Steele-Mortimer, O, Horiuchi, H, Alexandrov, K, Zerial, M	EMBO J.	1994
8164745	Membrane targeting of the small GTPase Rab9 is accompanied by nucleotide exchange Svejstrup, AB, Pfeffer, SR, Shapiro, AD, Soldati, T	Nature	1994
8631982	Mechanism of digeranylgeranylation of Rab proteins. Formation of a complex between monogeranylgeranyl-Rab and Rab escort protein Seabra, MC, Shen, F	J. Biol. Chem.	1996
21250943	TBC proteins: GAPs for mammalian small GTPase Rab? Fukuda, M	Biosci. Rep.	2011
7991565	Rab geranylgeranyl transferase catalyzes the geranylgeranylation of adjacent cysteines in the small GTPases Rab1A, Rab3A, and Rab5A Ericsson, LH, Gelb, MH, Farnsworth, CC, Seabra, MC, Glomset, JA	Proc. Natl. Acad. Sci. U.S.A.	1994
21330364	DENN domain proteins: regulators of Rab GTPases Dokainish, H, Marat, AL, McPherson, PS	J. Biol. Chem.	2011
25402849	Protein prenylation: enzymes, therapeutics, and biotechnology applications Palsuledesai, CC, Distefano, MD	ACS Chem. Biol.	2015
20466531	Rab GEFs and GAPs Lambright, DG, Barr, FA	Curr. Opin. Cell Biol.	2010
20512138	Membrane targeting mechanism of Rab GTPases elucidated by semisynthetic protein probes Oesterlin, LK, Tan, KT, Wu, YW, Alexandrov, K, Waldmann, H, Goody, RS	Nat. Chem. Biol.	2010
22251903	Illuminating the functional and structural repertoire of human TBC/RABGAPs Frasa, MA, Braga, VM, Ahmadian, MR, Koessmeier, KT	Nat. Rev. Mol. Cell Biol.	2012
22694141	Structure, regulation and cellular functions of Rab geranylgeranyl transferase and its cellular partner Rab Escort Protein Swiezewska, E, Gutkowska, M	Mol. Membr. Biol.	2012
16855591	TBC-domain GAPs for Rab GTPases accelerate GTP hydrolysis by a dual-finger mechanism Lambright, DG, Pan, X, Munson, M, Eathiraj, S	Nature	2006
19603039	Rab GTPases as coordinators of vesicle traffic Stenmark, H	Nat. Rev. Mol. Cell Biol.	2009
8662963	Nucleotide dependence of Rab geranylgeranylation. Rab escort protein interacts preferentially with GDP-bound Rab Seabra, MC	J. Biol. Chem.	1996
23898197	Membrane extraction of Rab proteins by GDP dissociation inhibitor characterized using attenuated total reflection infrared spectroscopy Goody, RS, Kötting, C, Itzen, A, Gerwert, K, Gavriljuk, K	Proc. Natl. Acad. Sci. U.S.A.	2013