Rab gefs and gaps. Cell Struct Funct 79, 61–79.

Rab gefs and gaps Article PubMed MATH Google Scholar May 11, 2010 · A complementary study analyzing the TBC domain Rab GAPs in human cells found that TBC1D30 was a GAP for Rab8A, and showed that Rab8A was the sole Rab enriched on primary cilia . Aug 1, 2019 · DOI: 10. Only two Rab-specific GEFs May 24, 2023 · The Parkinsons Disease associated kinase LRRK2 is proposed to act through phosphorylation of Rab proteins, most notably Rab10. P. Aug 8, 2009 · The Rab GAP cascade model offers several testable predictions: first, the GAP for the upstream Rab should bind to the GTP-bound form of the downstream Rab, but not stimulate its GTPase activity. Only two Rab-specific GEFs Sep 11, 2019 · Small GTPases are key regulators of cellular events, and their dysfunction causes many types of cancer. 8A ). The membrane recruitment mechanism for the Rab GAP Gyp1, which as noted above deactivates the yeast Rab1 ortholog Ypt1, illustrates a functional ‘Rab cascade’ in which the GAP for Ypt1, a Rab required for fusion of ER-derived vesicles with the cis-Golgi, is recruited to the Golgi through an effector binding interaction with active Ypt32, a Further potential for Rab protein modulation may lie in the targeting of other Rab effectors such as GEFs, GAPs, and GDIs. A role in macroautophagy regulation for different TRE2-BUB2-CDC16 (TBC) domain-containing RAB GAPs has been established. Small GTPases 9, 5–21 (2018). GAPs, Ran-GAPs, and Rab-GAPs act within their specific family of G proteins, whereas the unrelated Ras-GAPs and Rap-GAPs both act on proteins of the Ras family. Rab GAP proteins associate with a GTP-bound Rab and promote GTP hydrolysis, resulting in the GDP-bound inactive Rab and thus controlling the lifetime of Rab's active form. 2009 Aug 25;106(34) :14185-6. , 1998 ), Rab GAPs characteristically contain a TBC domain that catalyzes nucleotide hydrolysis by an arginine-glutamine two-finger Jul 18, 2016 · Impairment of GAPs or overexpression of GEFs can cause an increase in active Rab GTPases, influencing the recruitment of downstream effectors regulated by active Rab GTPases, then may regulate Aug 1, 2023 · Prenylated GDP-bound Rab is bound to GDI in the cytosol. @article{Lamber2019RabRB, title={Rab regulation by GEFs and GAPs during membrane traffic. GTPases are deactivated by GTPase-activating proteins (GAPs) and are activated by guanine-nucleotide exchange factors (GEFs). In this model, Rabs help to recruit GEFs and GAPs for the Rab proteins that function before and after themselves in a particular trafficking pathway like secretion or endocytosis . 97 The mechanisms by which these GEFs and GAPs regulate Rab GTPases are discussed, highlighting common themes and points of difference, and briefly outlining the cellular processes they regulate. The human genome encodes almost 70 Rabs (3); baker's yeast encodes just 11 (4). 4 ). Jan 1, 2014 · It is also noteworthy that the number of GEFs and GAPs varies greatly between small GTPases families, including small GTPases that are still orphans of GEFs and/or GAPs, found mostly in the Arf-like family (see approximate numbers for the human genome in Table 3. e. Aug 1, 2010 · They are regulated by a diverse group of structurally unrelated GDP-GTP exchange factors (GEFs), and a family of GTP-hydrolysis activating proteins (GAPs) containing the conserved TBC domain. Barr}, journal={Current opinion in cell biology}, year={2019}, volume={59}, pages={ 34-39 }, url={https://api Jul 15, 2009 · The coupling between Rab effectors and Rab regulators, best illustrated by the inclusion of Rab GEFs and GAPs in Rab effector complexes, not only ensures the wiring of positive-feedback loops and Jun 15, 2020 · Most Rab-GAPs identified to date are members of the Tre-2/Bub2/Cdc16 (TBC) domain-containing protein family and are encoded by ~ 40 genes in mammals [] (see Table S1). 72 In contrast, the Legionella pneumophila GAP LepB uses a 7 single Arg-finger comparable to other GAPs of small GTPases in conjunction with the cis-Gln provided by the Rab protein (Fig. Following activation by guanine‐nucleotide exchange factors (GEFs), each Rab binds a specific set of effector proteins that mediate the various An overview of Rab proteins is given with a focus on the current understanding of their regulation by GEFs, GAPs and GDI. Figure 1: Nucleotide and membrane cycling of Ypt/Rab GTPases. Their activity can be tightly controlled within cells: Regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), they switch between an active GTP-bound state and an inactive GDP- … Guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) regulate the activity of small guanine nucleotide-binding (G) proteins to control cellular functions. The intrinsic GTP The regulation of Rab35 activity by the connecdenn/DENND1 family of GEFs and the TBC1D10/EPI64 family of GTPase‐activating proteins will be described. They are regulated by a diverse group of structurally unrelated GDP-GTP exchange factors (GEFs), and a family of GTP-hydrolysis activating proteins (GAPs) containing the conserved TBC domain. GAPs stimulate GTP hydrolysis, which is followed by Rab extraction through GDI. TBC1D5 (a Rab7 GAP (Müller and Goody, 2018)), was identified The activity of RAB GTPases is coordinated by upstream factors, which include guanine nucleotide exchange factors (RAB GEFs) and RAB GTPase activating proteins (RAB GAPs). Many of these domains are protein or lipid interaction domains, indicating that Aug 7, 2005 · Although many studies have focused on the identification of effector proteins that bind to specific Rabs, far less is known about the GEFs and GAPs that control them. functions of Rabs, and we update the lists of GEFs, GAPs, effectors, and knockout (KO) phenotypes of mammalian Rabs. Release from GDI and GEF-mediated nucleotide exchange bring active GTP-bound Rabs onto the organelle surface. ceb. The GTPase switch is turned on by GEFs, which stimulate dissociation of the tightly bound GDP, and turned off by GAPs, which accelerate the intrinsically sluggish hydrolysis of GTP. Most Rab GAPs identified so far in eukaryote contain a catalytic α-helical TBC (Tre-2/Cdc16/Bub2) domain Citation 82,83 ( Fig. Mar 4, 2018 · Rab proteins are the major regulators of vesicular trafficking in eukaryotic cells. In at least one case, Vps9 and Rabex-5, GEFs for the Ypt/Rab homologs Ypt51 and Rab5, share significant sequence similarity. During vesicle membrane tethering Rab GTPases are activated by GEFs (guanine nucleotide exchange factors) and then inactivated by GAPs (GTPase activating proteins). Aug 1, 2019 · Rab GTPases and their regulatory proteins play a crucial role in vesicle-mediated membrane trafficking. Some of the most well-studied Rab GEFs are the large multi-subunit TRAnsport Protein Particle (TRAPP) complexes 4–9. 96 In addition to this, Ypt32 facilitates the proper localization and activity of the Ypt1 GAP, and Gyp1. Aug 8, 2009 · A study in this issue of PNAS shows that a Rab protein that functions in the yeast secretory pathway can inactivate an earlier-acting Rab by recruiting its cognate GTPase-activating protein (GAP). 2a). Rab proteins are key regulators of membrane traffic (1, 2). Many GAPs are found in the cytosol, suggesting that they have continual access to Rabs on membranes [ 6 , 7 ]. , 1997 ; Nagano et al. For their function Rabs, GEFs and GAPs need to be recruited onto the appropriate membrane. Recent evidence shows that in a … ABSTRACT. Jan 17, 2019 · 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). Defining the boundaries: Rab GEFs and GAPs Proc Natl Acad Sci U S A. At least for the yeast Golgi complex, it has been shown ( 5 , 6 ) that selective recruitment of the appropriate GEFs and GAPs generate a Ypt32p compartment that can exclude Rabs are GTP-binding proteins with conserved functions in membrane trafficking. M€uller and Roger S. Goody Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology Apr 6, 2019 · This cycle is tightly regulated by guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and, for the Rho and Rab sub-families, guanine nucleotide dissociation inhibitors (GDIs) (Figure 2). Rab reactivation is catalyzed by guanine nucleotide ex-change factors (GEFs) that speed re-lease of Rab-bound GDP, permitting rebinding of cytosolic GTP. S. Then, with the help of GTP … Jan 1, 2014 · Rab GEFs fall into a number of discrete families, the largest of which are the Vps9 domain, DENN and DENN domain-related proteins. Rab proteins are the major regulators of vesicular trafficking in eukaryotic cells. Rab functions beyond the simple effector-recruiting model are also emerging. Defining the boundaries: Rab GEFs and GAPs In addition to their conserved structures consisting of general motifs, Rab proteins harbor several short insertion amino acid sequences termed RabF and RabSF [51,52], which are used for interacting with Rab-specific regulators (GEFs and GAPs). May 11, 2010 · A complementary study analyzing the TBC domain Rab GAPs in human cells found that TBC1D30 was a GAP for Rab8A, and showed that Rab8A was the sole Rab enriched on primary cilia . Then, with the help of GTPase-activating proteins, the Rab con-verts GTP to GDP, terminating its function. Aug 1, 2019 · During vesicle membrane tethering Rab GTPases are activated by GEFs (guanine nucleotide exchange factors) and then inactivated by GAPs (GTPase activating proteins). Whereas GEFs and GAPs are specific for individual Ypt/Rabs, GDI is a generic chaperone for multiple Ypt/Rabs . Cell Struct Funct 79, 61–79. , 2009), central scaffolds that link different families of small GTPases. We have developed a method for assaying Rab-GAP activity in a physiological context, with dissociation of the Rab from the membrane serving as a readout for Rab-GAP activity. The low homology between Rab GEFs is probably the reason that for many Rabs, the corresponding GEFs are yet to be identified. The known Rab GEFs and GAPs typically fall into discrete families defined by conserved protein domains (Barr and Lambright, 2010). GEFs and GAPs therefore play a key role in the specific activation and inactiva-tion of Rab GTPases. Each TBC protein is thought to exert GAP activity on specific Rab family proteins, although their corresponding substrates have not been fully clarified []. Rab function is dictated by nucleotide binding: when GTP-bound, or “active ,” Rabs are anchored to membranes via C-terminal prenylation modifications and recruit effector proteins that control the formation, transport, and receipt of vesicles . }, author={Ekaterina P. For Ras, Rho, and Rab GTPases, this switch incorporates a membrane/cytosol alternation regulated by GDIs and GDI-like proteins. Given that membrane-binding status is a key consequence of Rab activation state, this assay will be useful for the study of a wide range of Rab/Rab-GAP pairs. However, all the yeast Ypt GEFs have homologs in higher eukaryotes. Rho and Rab families possess a third class of regulatory proteins, guanine nucleotide dissociation inhibitors, • GEFs and GAPs are deregulated in cancer by somatic mutation, changes in gene A great deal of recent work has been undertaken to assign the various Rab and GAP proteins into linked pathways called Rab cascades . Recent evidence suggests that these proteins may be potential therapeutic targets for developing drugs to treat various diseases, including cancer. Sep 1, 2015 · Rab GAPs turn Rab GTPases off by stimulating their ability to hydrolyze GTP into GDP. RabGAP1 ((TBC1D11); a Rab2, Rab4, Rab6, Rab11 and Rab36 GAP) was enriched to each Rab tested (Figure 3, Supplementary Table 1 and 2). These small GTPases located on the cytoplasmic surfaces of The results of these studies have included the identification and characterization of novel GEFs, GAPs, and effectors, as well as post-translational modifications, for example, phosphorylation, of Rabs. GEFs and GAPs have in common that they are usually multidomain proteins (Figure 1). Many of these domains are protein or lipid interaction domains, indicating that May 14, 2019 · Yet, we argue that studying the entire ARF family of GTPases together and in concert with the families of their GEFs and GAPs will provide substantially more information and is critical to our understanding of 1) sources of specificity and functional redundancies, 2) complexities resulting from one protein acting at multiple sites, 3) enigmas Apr 17, 2024 · Figure \(\PageIndex{8}\): The activity of Ras GAPs and GEFs, as well as various proteins interacting with Ras. Their activity can be tightly controlled within cells: Regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), they switch between an active GTP-bound state and an inactive GDP-bound state, interacting with downstream effector proteins only in the active state. Our data suggest that the Rgp1 amphipathic helix is involved in Golgi membrane Jan 5, 2017 · In this review we give an overview of Rab proteins with a focus on the current understanding of their regulation by GEFs, GAPs and GDI. It is best to use only the minimum amount of Rab-GAP necessary for Rab inactivation, especially when aiming to discern mechanisms of Rab-GAP recruitment or activity regulation. Dec 4, 2024 · Several Arf and Rab GEFs and GAPs are known to use amphipathic helices to bind to the Golgi membrane 35,46,47,48,49. This model predicts that GEFs The countercurrent cascades of GAPs and GEFs not only ensure that the appropriate downstream Rab is recruited but that the upstream Rab is concomitantly inactivated to delineate one compartment from another. Aug 1, 2013 · Rab activity is modulated in part by GTPase-activating proteins (GAPs), and many RabGAPs share a Tre-2/Bub2/Cdc16 (TBC) domain architecture, although the majority of TBC proteins remain poorly Jun 15, 2020 · The results of these studies have included the identification and characterization of novel GEFs, GAPs, and effectors, as well as post-translational modifications, for example, phosphorylation, of Rabs. (Continued ) Dec 4, 2020 · Essential to the regulation of Rab GTPases are the actions of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), which mediate Rab activation and inactivation Rabs, in turn, are regulated by specific guanine nucleotide exchange factors (GEFs), which catalyze the displacement of GDP and binding of GTP, as well as GTPase activating proteins (GAPs) that stimulate the slow intrinsic rate of GTP hydrolysis. 3b). Oct 13, 2017 · Novick discovered that the order (and thus polarity) of Rab GTPases along the secretory and endocytic pathways are established by their specific, cognate guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), which partner with one Rab to regulate the subsequent- and prior-acting Rabs. [Google Scholar] 29. Members of the different branches of the superfamily are regulated by GEFs and GAPs with structurally distinct catalytic domains 3, 4, 149 Jan 8, 2025 · Müller, M. For example, in yeast the Rab switch for trafficking through the late Golgi is ensured by the coordinated inactivation of Ypt1 and Rab GEFs fall into a number of discrete families, the largest of which are the Vps9 domain, DENN and DENN domain-related proteins. Other Rab GEF families, including TRAPP, Ric1-Rgp1, Mon1-Ccz1 and Hps1-Hps4, are comprised of two or more polypeptide chains. Because many Rab GTPases, including Rab5, hydrolyze GTP at a relatively high intrinsic rate, Rab GAPs might be less crucial than GEFs in general (Barr and Lambright, 2010). Active GTP-bearing Rabs are stabilized on membrane surfaces by binding to their cognate effector proteins (6). Proc Natl Acad Sci USA 106 , 14408–14413 (2009). Ishida M, Oguchi ME & Fukuda M (2016) Multiple types of guanine nucleotide exchange factors (GEFs) for Rab small GTPases. Lamber and Ann-Christin Siedenburg and Francis A. 1B), this mechanism would ensure homogeneity of distinct, Rab-generated, membrane microdomains. This process was shown to help delineate boundaries between Rab GTPases on membranes. Most Rab GAPs identified so far in eukaryote contain a catalytic α-helical TBC (Tre-2/Cdc16/Bub2) domain 82,83 ( Fig. Therefore, the search for new Rab-GEFs cannot rely on similarity with GEFs for other Rabs but must rely, at least in part, on similarity with yeast Ypt-GEFs. 03. Jan 16, 2011 · By analogy with data from other members of the Rab family, it seems conceivable that this GDP-to-GTP cycle could also be regulated in the case of Rab18 by specific GEFs, GTPase activator proteins (i. The intrinsic GTP May 24, 2023 · The Parkinsons Disease associated kinase LRRK2 is proposed to act through phosphorylation of Rab proteins, most notably Rab10. Their activity can be tightly controlled within cells: Regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), they switch between an active The Rab GAP cascade model offers several testable predictions: first, the GAP for the upstream Rab should bind to the GTP-bound form of the downstream Rab, but not stimulate its GTPase activity. GTPase-activating proteins (GAPs) or spontaneously because of intrinsic activity of the Rab ends the cycle. The known Rab GEFs and GAPs typically fall into dis-crete families defined by conserved protein domains (Barr and Lambright, 2010). Nov 24, 2010 · For the 20 human Rho GTPases there are 83 GEFs and 67 GAPs, and a subset of Rho GTPases are not likely to be regulated by GEFs and GAPs (such as RND3; also known as RHOE). To date, many Rab GEFs have been identified . , GDFs), although none of these proteins have been Jan 1, 2014 · Rab proteins (purple) directly interact with GAPs and GEFs (orange), which often show activity towards up or downstream Rab GTPases. ABSTRACT Rab proteins are the major regulators of vesicular trafficking in eukaryotic cells. By contrast, almost all known Rab GAPs possess a TBC1 domain. Other proteins—known as GAPs—lead to the inactivation of the Rab protein. Rabs are GTP-binding proteins with conserved functions in membrane trafficking. Molecular control of Rab activity by GEFs, GAPs and GDI. Jun 15, 2020 · Most Rab-GAPs identified to date are members of the Tre-2/Bub2/Cdc16 (TBC) domain-containing protein family and are encoded by ~ 40 genes in mammals [] (see Table S1). Proteins called guanine nucleotide exchange factors, or GEFs for short, activate the Rab protein by promoting the release of GDP and the binding of GTP. For Ras, Rho, and Rab GTPases, this switch incorporates a membrane/cytosol alternation regulated Oct 1, 2022 · The Rab protein is transmitted to the membrane through guanine nucleotide exchange factors (GEFs) and in some cases may need the help of GTPase-activating proteins (GAPs) [1]. May 1, 2010 · Guanine nucleotide exchange factors (GEFs) act as the primary determinants of Rab localization by activating and stabilizing their Rab substrates on specific organelle and vesicle membranes. TBC-domain GAPs were thus shown to act via a dual-finger mechanism (Fig. However, these activities are too low to allow efficient and rapid cycling between their active GTP-bound and inactive GDP-bound states. This study also identified EVI5-like as the GAP for Rab23, which known to have a function at cilia during development, and TBC1D7 as the GAP for Rab17, which belongs to Sep 1, 2009 · The cycle is controlled by two regulatory enzymes: specific guanine nucleotide exchange factors (GEFs)-catalyze the exchange GDP for GTP in Rab GTPases (48), and GTPase-activating proteins (GAPs Aug 1, 2010 · It is demonstrated for the first time that the ubiquitin-proteasome degradation pathway regulates a Rab GTPase, and it is defined that Rab35 is required for axonal outgrowth and its protein levels are negatively regulated by p53-related protein kinase (PRPK), and microtubule-associated protein 1B (MAP1B) interacts with PRPK, preventing PRPK-dependent Rab35 proteasome degrade. Second, the interaction with the downstream Rab should serve to recruit the GAP to the compartment marked by that Rab. Rab GTPases are key regulators of membrane traffic activated on the surface of organelle and vesicle membranes during vesicle trafficking events, cell polarisation and autophagy. Dec 1, 1997 · GAPs As with GEFs, a large number of GTPase-activating proteins (GAPs) have been identified, and each subfamily of Ras-related proteins, such as Ras, Rac/Rho, Rab and Aft, have their own version of a specific GAP with its own conserved sequence elements [3]. 2019. Jun 1, 2007 · Guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) regulate the activity of small guanine nucleotide-binding (G) proteins to control cellular functions. Sep 11, 2019 · Small GTPases are key regulators of cellular events, and their dysfunction causes many types of cancer. There are over 60 Rabs in humans and only a subset has been analyzed in any Aug 25, 2009 · Defining the boundaries: Rab GEFs and GAPs. 94, 95 Moreover, these small GTPases were found in the same Rab cascade in yeast: the GEF of Ypt32 is a putative effector of Ypt1. GEFs and GAPs accelerate and regulate these intrinsic activities. Aug 7, 2005 · Although many studies have focused on the identification of effector proteins that bind to specific Rabs, far less is known about the GEFs and GAPs that control them. In a number of cases, a GEF is recruited to the membrane by an upstream Rab for activation of a downstream Rab, forming a Rab cascade (Fig. Most Rab proteins interact with specific effector proteins that regulate distinct intracellular transport processes, such as intracellular protein trafficking, the trans Aug 29, 2021 · Rab Regulation: Challenges in identifying Rab GEFs and GAPs have been different because while GEFs for individual Rabs do not share sequence similarity (e. Most (but not all) Rab GAPs are distinguished by the presence of a TBC1 domain. As shown in Figure \(\PageIndex{4}\), there are 20 Rho G proteins but about 80 GEFs and 70 GAPs for them. Open in a new tab GAPs, Ran-GAPs, and Rab-GAPs act within their specific family of G proteins, whereas the unrelated Ras-GAPs and Rap-GAPs both act on proteins of the Ras family. All Rabs participate in a GTPase cycle, in which GEFs (Guanine The GEFs and GAPs are recruited to distinct organelles by proteins and lipids characteristic to each organelle to facilitate the establishment of functional Rab domains on the membrane. Crossref Feb 1, 2017 · Europe PMC is an archive of life sciences journal literature. & Goody, R. Recent evidence shows that in addition to activating and inactivating Rab GTPases, both Rab GEFs and GAPs directly contribute to membrane tethering events during vesicle traffic. 22 In the past, a variety of different Rab GEFs have been identified (summarized in Table 1), including the Vps923 and DENN domain24 families of Rab GEFs as well as several other unrelated proteins. 25 Barr F & Lambright DG (2010) Rab GEFs and GAPs. Small GTPases use GDP/GTP alternation to actuate a variety of functional switches that are pivotal for cell dynamics. Aug 25, 2009 · FE Rivera-Molina, PJ Novick, A Rab GAP cascade defines the boundary between two Rab GTPases on the secretory pathway. 70 The general role of the Gln (whether provided by the GAP or the Rab Aug 25, 2009 · A study in this issue of PNAS shows that a Rab protein that functions in the yeast secretory pathway can inactivate an earlier-acting Rab by recruiting its cognate GTPase-activating protein (GAP). This analysis has provided strong evidence that positive and negative feedback loops in this system mediated by Rab GEFs and GAPs result in bistability in the form of a cut-out switch, so that Rab5 accumulation is followed by an abrupt transition at which Rab5 is rapidly lost and Rab7 accumulates (Del Conte-Zerial et al. The Vps9 and DENN families are two particularly large Rab-specific GAPs counteract the action of Rab-specific GEFs and reverse the process of trapping Rabs on membranes. With the exception of the Rab3GAP1/2 proteins ( Fukui et al. In general, GEFs turn on signaling by catalyzing the exchange from G-protein-bound GDP to GTP, whereas GAPs terminate signaling by inducing GTP hydrolysis. Yet, despite the potential for their targeting, the identification of these effectors is generally lacking, particularly for GEFs, for which there exists a significant proportion of Rab family members without a Jun 22, 2012 · a | A conceptual diagram of RAB effector recruitment of specific RAB guanine nucleotide exchange factors (GEFs) or GTPase-activating proteins (GAPs) for consecutive RABs that are involved in During vesicle membrane tethering Rab GTPases are activated by GEFs (guanine nucleotide exchange factors) and then inactivated by GAPs (GTPase activating proteins). Here we discuss our current understanding of how distinct families of GEFs and GAPs control Rab function based on recent structural studies that shed light on their mechanism of action, and cell biological studies identifying the cellular trafficking pathways that they act in. GEFs and GAPs are multidomain proteins that are regulated Aug 5, 2016 · Rabs, in turn, are regulated by specific guanine nucleotide exchange factors (GEFs), which catalyze the displacement of GDP and binding of GTP, as well as GTPase activating proteins (GAPs) that stimulate the slow intrinsic rate of GTP hydrolysis. 1). Dec 26, 2013 · Rab GTPases are activated by at least four distinct types of Rab GEFs (a subfamily that carry a Vps9 domain or a DENN domain, the TRAPP complex, and Sec2) and downregulated by Rab GAPs belonging to a large family of TBC (Tre2/Bub2/Cdc16) domain-containing proteins. g. Dec 14, 2022 · Rab GTPases are key drivers of eukaryotic vesicle trafficking [1, 2]. REVIEW Molecular control of Rab activity by GEFs, GAPs and GDI Matthias P. [PMC free article] [Google Scholar] 28. 004 Corpus ID: 113407655; Rab regulation by GEFs and GAPs during membrane traffic. Then, with the help of GTPase-activating proteins, the Rab converts GTP to GDP, terminating its function. Dec 4, 2020 · Essential to the regulation of Rab GTPases are the actions of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), which mediate Rab activation and inactivation, respectively 1–3. We recommend performing an initial titration of purified Rab-GAP to determine the minimum concentration required for robust Rab activation within the 5-minute reaction time. , 2008). Recent structural and cell biological studies shed new light on the mechanisms of Rab GEF and GAP action, and the cellular trafficking pathways they act in. 1016/j. However, if a given Rab also recruits a GAP to inactivate another Rab (Fig. Following activation by guanine-nucleotide exchange factors (GEFs), each Rab binds a specific set of effector proteins that mediate the various downstream functions of that Rab. TRAPP complexes are common GEFs of the yeast homologs of RAB1 and RAB11, Ypt1 and Ypt31/32, respectively. The maturation of membrane compartments through cascading RAB pathways is estab - lished in both exocytosis and endo cytosis3. These results combined with interaction of Gyp1 and Gyp6 with Ypt32 suggest that Rab-GAP cascades coordinate sequential localization of Ypt1, Ypt6, and Ypt32 on the Golgi [22, 33]. 3a). Jun 1, 2007 · GEFs and GAPs are multidomain proteins that are regulated by extracellular signals and localized cues that control cellular events in time and space. , GDIs) and GDI displacement factors (i. GTPases bind to the guanine nucleotides GDP and GTP with picomolar affinity and a very slow off-rate, so the intrinsic rate of Feb 11, 2014 · Binding to a molecule called GDP makes the Rab protein inactive, while binding to GTP makes it active. Thereby Rab cascades are created, ensuring vectorial flow of membranes and proteins within the cell. specified through the recruitment of RAB GEFs and GAPs as RAB effectors (FIG. It is likely that more regulators remain to be discovered, although it is also Aug 19, 2009 · Europe PMC is an archive of life sciences journal literature. Rab proteins and their known GEFs and GAPs. GEFs and GAPs are multidomain proteins that are regulated provided by specific GEF and GAPs regulators [3, 4]. , a Rab GEF domain), Rab GAPs do share one of two such signatures, termed GYP/TBC or DENN. Aug 25, 2009 · A study in this issue of PNAS shows that a Rab protein that functions in the yeast secretory pathway can inactivate an earlier-acting Rab by recruiting its cognate GTPase-activating protein (GAP). May 11, 2010 · Abstract Free full text Full text links; Citations & impact Rab GEFs and GAPs. Rab GTPases and their regulatory proteins play a crucial role in vesicle-mediated membrane trafficking. Aug 1, 2019 · Furthermore, we find that the concomitant loss of LET-502 and another CED-10 effector, TBC-2/RAB-5-GAP, results in an endosomal buildup of RAB-5, indicating that CED-10 directs TBC-2-mediated RAB Apr 10, 2019 · During vesicle membrane tethering Rab GTPases are activated by GEFs (guanine nucleotide exchange factors) and then inactivated by GAPs (GTPase activating proteins). This study also identified EVI5-like as the GAP for Rab23, which known to have a function at cilia during development, and TBC1D7 as the GAP for Rab17, which belongs to The GTPase switch is turned on by GEFs, which stimulate dissociation of the tightly bound GDP, and turned off by GAPs, which accelerate the intrinsically sluggish hydrolysis of GTP. Co-evolution of Rab GEFs and vesicle coat complexes Phylogenetic analysis reconstructing the evolution of Rab GTPases suggests that the last eukaryotic common ancestor possessed 20 such GTPases and had all of the core organelles associated with eukaryotic cells today – endoplasmic reticulum, tion by guanine-nucleotide exchange factors (GEFs), each Rab binds a specific set of effector proteins that medi-ate the various downstream functions of that Rab. Aug 10, 2019 · Interestingly, deletion of Gyp1, a Ypt1 GAP, or Gyp6, the GAP for Ypt6, delayed the removal of Ypt1 or Ypt6, respectively, from the Golgi. They serve as molecular switches by cycling between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound states. It may seem crazy but the number of GEFs and GAPs is greater than the number of small G proteins. Rho GTPases are Aug 1, 2013 · Following activation by guanine-nucleotide exchange factors (GEFs), each Rab binds a specific set of effector proteins that mediate the various downstream functions of that Rab. May 2, 2024 · Cooperation with their effectors, such as GEFs, GAPs and guanine dissociation inhibitors (GDIs) together with tethering factors and Soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs), Rab proteins are crucial for mediating vesicular traffick from donor membrane budding toward acceptor membrane fusion as well as specialized pathways regulating cell growth, survival Dec 10, 2018 · A conformational transition is also regulated through interactions with coat proteins, as well as Rab GEFs and Arf GAPs (Chaineau et al. Aug 1, 2010 · Rabs are GTP-binding proteins with conserved functions in membrane trafficking. Rabs are the largest family of small GTPases and are master regulators of membrane trafficking. , GAPs), guanine dissociation inhibitors (i. Recent structural and cell biological studies shed new light on the mechanisms of Rab GEF and GAP action, and the cellular trolled manner. . Curr Opin Cell Biol 22, 461–470. Rabs undergo a cycle of Aug 19, 2009 · Europe PMC is an archive of life sciences journal literature. Nomenclature of mammalian Rab genes Typical Rab genes encode a small GTPase consisting of around 200–250 amino acids, and approximately 60 Rab genes have been identified in mammals to date (Table 1) [5–8].