Illuminating the functional and structural repertoire of human TBC/RABGAPs

Frasa, Marieke A. M.; Koessmeier, Katja T.; Ahmadian, Mohammad Réza; Braga, Vania

doi:10.1038/nrm3267

Cited by 137 publications

(124 citation statements)

References 76 publications

Supporting

Mentioning

121

Contrasting

Unclassified

Order By: Relevance

“…TBC domains usually function as GAPs for members of the Rab family of small G-proteins using a dual-finger mechanism (30,31). Although the TBC1D7 TBC domain (residues 50 -231) does not contain the two most critical catalytic ("finger") residues (25, 31), TBC1D7 was shown to specifically inac-* This work was supported by CAS Grant XDB08010303, and the Department of Defense Grant W81XWH-13-1-0059 (TS120073) (to W.…”

Section: Tuberous Sclerosis Complex (Tsc)mentioning

confidence: 99%

Structural Basis of the Interaction between Tuberous Sclerosis Complex 1 (TSC1) and Tre2-Bub2-Cdc16 Domain Family Member 7 (TBC1D7)

Qin

Wang

Hoogeveen‐Westerveld

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Mutations in TSC1 or TSC2 cause tuberous sclerosis complex (TSC), an autosomal dominant disorder characterized by the occurrence of benign tumors in various vital organs and tissues. TSC1 and TSC2, the TSC1 and TSC2 gene products, form the TSC protein complex that senses specific cellular growth conditions to control mTORC1 signaling. TBC1D7 is the third subunit of the TSC complex, and helps to stabilize the TSC1-TSC2 complex through its direct interaction with TSC1. Homozygous inactivation of TBC1D7 causes intellectual disability and megaencephaly. Here we report the crystal structure of a TSC1-TBC1D7 complex and biochemical characterization of the TSC1-TBC1D7 interaction. TBC1D7 interacts with the C-terminal region of the predicted coiled-coil domain of TSC1. The TSC1-TBC1D7 interface is largely hydrophobic, involving the ␣4 helix of TBC1D7. Each TBC1D7 molecule interacts simultaneously with two parallel TSC1 helices from two TSC1 molecules, suggesting that TBC1D7 may stabilize the TSC complex by tethering the C-terminal ends of two TSC1 coiled-coils.Tuberous sclerosis complex (TSC) 4 is a multisystem genetic disease that is characterized by the development of hamartomas or benign tumors in various organs, including skin, brain, and kidneys, and is frequently associated with epilepsy, intellectual disability, and autism (1, 2). TSC is caused by mutations to either of two genes, TSC1 and TSC2, which encode for proteins hamartin (TSC1) and tuberin (TSC2), respectively. TSC1 and TSC2 form a protein complex that acts as a GTPase-activating protein (GAP) for the small G-protein Rheb, which in turn serves as a crucial activator of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). The TSC complex is a tumor suppressor, inhibiting the Rheb-mTORC1-dependent stimulation of anabolic metabolism and cell growth (2-11). TSC2 contains a GAP domain and is the catalytic subunit of the complex. TSC1 is believed to enhance TSC2 function by activating TSC2 GAP activity, stabilizing TSC2, and/or maintaining the correct intracellular localization of the TSC complex (12-19). Recent work indicates that TSC1 might also have TSC2-independent activities in the cell (20 -22).Tre2-Bub2-Cdc16 domain family member 7 (TBC1D7) is a TSC1-binding protein (23-25), and has been recently identified as the third subunit of the TSC complex (25). TSC1, TSC2, and TBC1D7 form the core of the TSC protein complex in the cell, which migrates in size exclusion chromatography with a peak mass of ϳ2 MDa (26). Consistent with its important role in the TSC protein complex, knockdown of TBC1D7 results in decreased association of TSC1 and TSC2, leading to decreased Rheb-GAP activity, increased mTORC1 signaling, delayed induction of autophagy, and enhanced cell growth under poor growth conditions (25). Intriguingly, overexpression of TBC1D7 was also reported to increase mTORC1 activity (23). TBC1D7 mutations have not been found in TSC patients, but homozygous loss of TBC1D7 causes intellectual disability and megalencephaly, a developmental disorder a...

show abstract

Section: Tuberous Sclerosis Complex (Tsc)mentioning

confidence: 99%

Structural Basis of the Interaction between Tuberous Sclerosis Complex 1 (TSC1) and Tre2-Bub2-Cdc16 Domain Family Member 7 (TBC1D7)

Qin

Wang

Hoogeveen‐Westerveld

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In addition, the active site of many small GTPases is completed by a catalytic "arginine finger" that is used, e.g., by Ras-, Rho-, and RabGAPs, but is not needed for catalysis in Ran and Rap. Conventional TBC domains possess conserved arginine and glutamine residues (2,11). In the case of activation of Rab33 (mouse) by the yeast GAP Gyp1, it was shown that a glutamine residue of Gyp1 (termed trans-glutamine) positions the water molecule rather than the conserved glutamine in Rab33 (termed cis-glutamine) (11).…”

mentioning

confidence: 99%

“…Interaction with effectors takes place in the GTPbound "on" state, and the inactivation occurs via GTP hydrolysis to GDP; this is catalyzed by GTPase activating proteins (GAPs), thereby downregulating the GTPase. Most RabGAPs contain Tre2-Bub2-Cdc16 (TBC) domains, and accelerate the intrinsic GTP hydrolysis rate up to 10 5 -fold (2,3). As regulators of Rabdependent pathways, RabGAPs are involved in a number of diseases, contributing to viral and bacterial infection, cancer development, predisposition to obesity, and others (1,2).…”

mentioning

confidence: 99%

“…Most RabGAPs contain Tre2-Bub2-Cdc16 (TBC) domains, and accelerate the intrinsic GTP hydrolysis rate up to 10 5 -fold (2,3). As regulators of Rabdependent pathways, RabGAPs are involved in a number of diseases, contributing to viral and bacterial infection, cancer development, predisposition to obesity, and others (1,2). Therefore, detailed insight into the RabGAP-mediated catalysis with highest possible spatiotemporal resolution is of great interest, and is an important prerequisite for the design of small molecules for molecular therapy.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Catalytic mechanism of a mammalian Rab·RabGAP complex in atomic detail

Gavriljuk

Gazdag

Itzen

et al. 2012

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

View full text Add to dashboard Cite

Rab GTPases, key regulators of vesicular transport, hydrolyze GTP very slowly unless assisted by Rab GTPase-activating proteins (RabGAPs). Dysfunction of RabGAPs is involved in many diseases. By combining X-ray structure analysis and time-resolved FTIR spectroscopy we reveal here the detailed molecular reaction mechanism of a complex between human Rab and RabGAP at the highest possible spatiotemporal resolution and in atomic detail. A glutamine residue of Rab proteins (cis-glutamine) that is essential for intrinsic activity is less important in the GAP-activated reaction. During generation of the RabGAP·Rab:GTP complex, there is a rapid conformational change in which the cis-glutamine is replaced by a glutamine from RabGAP (trans-glutamine); this differs from the RasGAP mechanism, where the cis-glutamine is also important for GAP catalysis. However, as in the case of Ras, a trans-arginine is also recruited to complete the active center during this conformational change. In contrast to the RasGAP mechanism, an accumulation of a state in which phosphate is bound is not observed, and bond breakage is the ratelimiting step. The movement of trans-glutamine and trans-arginine into the catalytic site and bond breakage during hydrolysis are monitored in real time. The combination of X-ray structure analysis and time-resolved FTIR spectroscopy provides detailed insight in the catalysis of human Rab GTPases.

show abstract

“…The conserved arginine and glutamine finger structures in the TBC domain were shown to be required for the GAP activity of the TBC domain-containing proteins, and the mutations of the two amino acids can abolish the GAP activity (28,47,48). We examined the effects of the corresponding mutant forms of EPI64B that bear the two respective point mutations.…”

Section: Discussionmentioning

confidence: 99%

EPI64B Acts as a GTPase-activating Protein for Rab27B in Pancreatic Acinar Cells

Hou

Tolmachova

Ernst

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: A potential GTPase-activating protein (GAP) regulates the activity of Rab27B in pancreatic acinar cells. Results: Overexpression of EPI64B specifically decreases the level of active Rab27B and enhances secretion. Conclusion: EPI64B acts as a Rab27B GAP in pancreatic acinar cells and regulates secretion. Significance: Deciphering functions of EPI64B can deepen our understanding in how Rab27B is regulated.

show abstract

Illuminating the functional and structural repertoire of human TBC/RABGAPs

Cited by 137 publications

References 76 publications

Structural Basis of the Interaction between Tuberous Sclerosis Complex 1 (TSC1) and Tre2-Bub2-Cdc16 Domain Family Member 7 (TBC1D7)

Structural Basis of the Interaction between Tuberous Sclerosis Complex 1 (TSC1) and Tre2-Bub2-Cdc16 Domain Family Member 7 (TBC1D7)

Catalytic mechanism of a mammalian Rab·RabGAP complex in atomic detail

EPI64B Acts as a GTPase-activating Protein for Rab27B in Pancreatic Acinar Cells

Contact Info

Product

Resources

About