TBC domain

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The Rab cycle in membrane trafficking: The cycle between the GTP-bound inactive state and the GTP- bound active state is led by the Rab protein and regulated by an activating enzyme GEF and an inactivating enzyme GAP which in this case could be the TBC protein. Hereafter, the activated form of Rab, GTP-bound, is incorporated to a specific organelle or vesicle and promotes its transport by interacting with a specific effector molecule. GTPase-activating proteins (GAPs) limit the duration of the active state and accelerate the slow intrinsic rate of GTP hydrolysis. Esquema rab.jpg
The Rab cycle in membrane trafficking: The cycle between the GTP-bound inactive state and the GTP- bound active state is led by the Rab protein and regulated by an activating enzyme GEF and an inactivating enzyme GAP which in this case could be the TBC protein. Hereafter, the activated form of Rab, GTP-bound, is incorporated to a specific organelle or vesicle and promotes its transport by interacting with a specific effector molecule. GTPase-activating proteins (GAPs) limit the duration of the active state and accelerate the slow intrinsic rate of GTP hydrolysis.

The TBC domain is an evolutionarily conserved protein domain found in all eukaryotes. It is approximately 180 to 200 amino acids long. The domain is named for its initial discovery in the proteins Tre-2, Bub2, and Cdc16.

Contents

TBC family members act as GTPase-activating proteins (GAPs) for small GTPases in regulating the cell cycle. For example, Rab activity is modulated in part by GAPs, and many RabGAPs share a Tre2/Bub2/Cdc16(TBC)-domain architecture, suggesting that TBC domain-containing proteins may behave similarly.

Examples

USP6 and CDC16 contain TBC domains. In addition, all proteins in the TBC family contain this domain:

Functions

TBC mainly functions as a specific Rab GAP (GTPases activating proteins) by being used as tools to inactivate specific membrane trafficking events. GAPs serve to increase GTPase activity by contributing the residues to the active site and promoting conversion from GTP to GDP form. Such activity of TBC proteins does not always require a close physical interaction although few TBC proteins have shown clear GAP activity towards their binding Rabs. [2] Rab families contribute to defining organelles and controlling specificity and rate of transport through individual pathways. Therefore, TBC Rab-GAPS are essential regulators of intracellular and membrane transports as well as central participants in signal transduction. Nevertheless, not all TBC may have a primary role as a Rab-GAP and conversely, not all Rab-GAP contain TBC. In addition, the fact that this family has been poorly studied makes it then further complicated.

Evolution and research

Phylogenetic analysis has provided insight into the evolution of the TBC family. ScrollSaw was implemented as a recent strategy to overcome poor resolution between TBC genes found in standard phylogenetic strategies during initial reconstructions. [3] Significantly, the TBC domain is nearly always smaller than the Rab cohort in any individual genome, suggesting Rab/TBC coevolution. Twenty-one putative TBC sub-classes were founded and identified as a seven robust and two moderately supported clades.

Moreover, there has also been systematic analysis in order to identify the target Rabs of TBC proteins. It was, at first, based on the physical interaction between the TBC domain and its substrate Rab. For instance Barr and his coworkers found a specific interaction between RUTBC3/RabGAP-5 and Rab5A that activates the GTPase activity of Rab5 isoform. Similarly other research has shown that, among other important aspects, the TBC-Rab interaction alone is insufficient to determine the target of TBC proteins. However, there has been a second approach to identifying the target Rabs of TBC by investigating their in vitro GAP activity. Yet there has been similar discrepancies between this findings of different investigators which can be found in literature and may be attributable to differences between methods of in vitro . In addition, research has shown that TBC proteins are associated with some human diseases. For example, a dysfunction of TBC1D1 and TBC1D4 directly affects insulin actions and glucose uptake. Causing overweight or leanness due to the fact that this two family members of TBC regulate insulin-stimulated GLUT4 translocation to the plasma membrane in mammals. Furthermore, many of them have been shown to be associated with cancer, but the exact mechanism by which they are associated with this illness remains largely unknown. Therefore, there’s still much research needed to be done on this biological topic.

Related Research Articles

GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a protein domain common to many GTPases.

Small GTPases, also known as small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotrimeric G-proteins, but unlike the alpha subunit of G proteins, a small GTPase can function independently as a hydrolase enzyme to bind to and hydrolyze a guanosine triphosphate (GTP) to form guanosine diphosphate (GDP). The best-known members are the Ras GTPases and hence they are sometimes called Ras subfamily GTPases.

<span class="mw-page-title-main">Guanine nucleotide exchange factor</span> Proteins which remove GDP from GTPases

Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity. Some GEFs can activate multiple GTPases while others are specific to a single GTPase.

<span class="mw-page-title-main">RAB8A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-8A is a protein that in humans is encoded by the RAB8A gene.

<span class="mw-page-title-main">ARFGAP1</span> Protein-coding gene in the species Homo sapiens

ADP-ribosylation factor GTPase-activating protein 1 is an enzyme that in humans is encoded by the ARFGAP1 gene. Two transcript variants encoding different isoforms have been found for this gene.

<span class="mw-page-title-main">RhoG</span> Protein-coding gene in the species Homo sapiens

RhoG is a small monomeric GTP-binding protein, and is an important component of many intracellular signalling pathways. It is a member of the Rac subfamily of the Rho family of small G proteins and is encoded by the gene RHOG.

<span class="mw-page-title-main">RAB1B</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-1B is a protein that in humans is encoded by the RAB1B gene.

<span class="mw-page-title-main">TBC1D4</span> Protein-coding gene in the species Homo sapiens

AS160, which was originally known as TBC1 domain family member 4 (TBC1D4), is a Rab GTPase-activating protein that in humans is encoded by the TBC1D4 gene.

<span class="mw-page-title-main">RICS (gene)</span> Protein-coding gene in the species Homo sapiens

Rho GTPase-activating protein 32 is a protein that in humans is encoded by the RICS gene. RICS has two known isoforms, RICS that are expressed primarily at neurite growth cones, and at the post synaptic membranes, and PX-RICS which is more widely expressed in the endoplasmic reticulum, Golgi apparatus and endosomes. The only known domain of the RICS is the RhoGAP domain, whilst PX-RICS has an additional Phox homology and SH3 domain.

<span class="mw-page-title-main">TBC1D1</span> Protein-coding gene in the species Homo sapiens

TBC1 domain family member 1 is a protein that in humans is encoded by the TBC1D1 gene.

<span class="mw-page-title-main">TBC1D3</span> Protein-coding gene in the species Homo sapiens

TBC1 domain family member 3E/3F is a protein that in humans is encoded by the TBC1D3F gene.

<span class="mw-page-title-main">RAB40A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-40A is a protein that in humans is encoded by the RAB40A gene.

<span class="mw-page-title-main">GAPVD1</span> Protein-coding gene in the species Homo sapiens

GTPase activating protein and VPS9 domains 1, also known as GAPVD1, Gapex-5 and RME-6 is a protein which in humans is encoded by the GAPVD1 gene.

ELMO is a family of related proteins involved in intracellular signalling networks. These proteins have no intrinsic catalytic activity and instead function as adaptors which can regulate the activity of other proteins through their ability to mediate protein-protein interactions.

GTPase-activator protein for Ras-like GTPase is a family of evolutionarily related proteins. Ras proteins are membrane-associated molecular switches that bind GTP and GDP and slowly hydrolyze GTP to GDP. This intrinsic GTPase activity of ras is stimulated by a family of proteins collectively known as 'GAP' or GTPase-activating proteins. As it is the GTP bound form of ras which is active, these proteins are said to be down-regulators of ras.

<span class="mw-page-title-main">SGSM2</span> Protein-coding gene in the species Homo sapiens

Small G protein signaling modulator 2 is a protein that in humans is encoded by the SGSM2 gene.

<span class="mw-page-title-main">RABGAP1</span> Protein-coding gene in the species Homo sapiens

RAB GTPase activating protein 1 is a protein in humans that is encoded by the RABGAP1 gene.

<span class="mw-page-title-main">PLEKHG5</span> Protein-coding gene in the species Homo sapiens

Pleckstrin homology domain containing, family G member 5 (PLEKHG5) is a protein that in humans is encoded by the PLEKHG5 gene. Eight transcript variants encoding different isoforms have been found for this gene.

<span class="mw-page-title-main">TBC1D24</span> Protein-coding gene in the species Homo sapiens

TBC1 domain family, member 24 is a protein that in humans is encoded by the TBC1D24 gene.

<span class="mw-page-title-main">EVI5L</span> Protein-coding gene in the species Homo sapiens

EVI5L is a protein that in humans is encoded by the EVI5L gene. EVI5L is a member of the Ras superfamily of monomeric guanine nucleotide-binding (G) proteins, and functions as a GTPase-activating protein (GAP) with a broad specificity. Measurement of in vitro Rab-GAP activity has shown that EVI5L has significant Rab2A- and Rab10-GAP activity.

References

  1. ↑ Rowlands AG, Panniers R, Henshaw EC (1988). "The catalytic mechanism of guanine nucleotide exchange factor action and competitive inhibition by phosphorylated eukaryotic initiation factor 2". The Journal of Biological Chemistry. 263 (12): 5526–33. PMID   3356695.
  2. ↑ Bos JL, Rehmann H, Wittinghofer A (2007). "GEFs and GAPs: critical elements in the control of small G proteins". Cell. 129 (5): 865–77. doi: 10.1016/j.cell.2007.05.018 . PMID   17540168. S2CID   15798389.
  3. ↑ Gabernet-Castello C, O'Reilly AJ, Dacks JB, Field MC (2013). "Evolution of Tre-2/Bub2/Cdc16 (TBC) Rab GTPase-activating proteins". Molecular Biology of the Cell. 24 (10): 1574–83. doi:10.1091/mbc.E12-07-0557. PMC   3655817 . PMID   23485563.
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