RAB GEFs exchange GTP for GDP on RABs

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Homo sapiens
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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, K├Âtting, C, Itzen, A, Gerwert, K, Gavriljuk, K

Proc. Natl. Acad. Sci. U.S.A. 2013
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