TBC Domain
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The TBC domain is an evolutionarily conserved
protein domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...
found in all
eukaryotes The eukaryotes ( ) constitute the domain of Eukaryota or Eukarya, organisms whose cells have a membrane-bound nucleus. All animals, plants, fungi, seaweeds, and many unicellular organisms are eukaryotes. They constitute a major group of ...
. It is approximately 180 to 200
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s long. The domain is named for its initial discovery in the proteins Tre-2, Bub2, and Cdc16. TBC family members act as
GTPase-activating protein GTPase-activating proteins or GTPase-accelerating proteins (GAPs) are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event. GAPs are a ...
s (GAPs) for small
GTPases 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 pro ...
in regulating the
cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
. For example,
Rab Rab may refer to: Places * Rab (island), an island in Croatia * Rab (town), on the island of Rab * Ráb, the Slovak name of Győr, a city in Hungary * Rąb, a village in Poland People * Rab (surname), includes a list of people with the n ...
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 Ubiquitin carboxyl-terminal hydrolase 6 (USB6), also termed TRE17 and Tre-2, is a deubiquitinating enzyme that in humans is encoded by the hominid (i.e. found only in primates) ''USP6'' gene located at band 13.2 on the short (i.e. "p") arm of ch ...
and
CDC16 Cell division cycle protein 16 homolog is a protein that in humans is encoded by the ''CDC16'' gene. Function This gene encodes a component protein of the APC complex, which is composed of eight proteins and functions as a protein ubiquitin l ...
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 Membrane vesicle trafficking in eukaryotic animal cells involves movement of biochemical signal molecules from synthesis-and-packaging locations in the Golgi body to specific release locations on the inside of the plasma membrane of the secretory c ...
events.
GAPs Gaps is a member of the Montana group of Patience games, where the goal is to arrange all the cards in suit from Deuce (a Two card) to King. Other solitaire games in this family include Spaces, Addiction, Vacancies, Clown Solitaire, Paganini, ...
serve to increase
GTPase 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 ...
activity by contributing the residues to the active site and promoting conversion from GTP to
GDP Gross domestic product (GDP) is a monetary measure of the total market value of all the final goods and services produced and rendered in a specific time period by a country or countries. GDP is often used to measure the economic performance o ...
form. Such activity of TBC
proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, re ...
does not always require a close physical interaction although few TBC proteins have shown clear GAP activity towards their binding Rabs. Rab families contribute to defining
organelle In cell biology, an organelle is a specialized subunit, usually within a cell (biology), cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as Organ (anatomy), organs are to th ...
s and controlling specificity and rate of transport through individual pathways. Therefore, TBC Rab-GAPS are essential
regulators Regulator may refer to: Technology * Regulator (automatic control), a device that maintains a designated characteristic, as in: ** Battery regulator ** Pressure regulator ** Diving regulator ** Voltage regulator * Regulator (sewer), a control de ...
of intracellular and
membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...
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 In biology, phylogenetics () is the study of the evolutionary history of life using observable characteristics of organisms (or genes), which is known as phylogenetic inference. It infers the relationship among organisms based on empirical data ...
has provided insight into the
evolution Evolution is the change in the heritable Phenotypic trait, characteristics of biological populations over successive generations. It occurs when evolutionary processes such as natural selection and genetic drift act on genetic variation, re ...
of the TBC family. ScrollSaw was implemented as a recent strategy to overcome poor resolution between TBC
genes In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
found in standard phylogenetic strategies during initial reconstructions. Significantly, the TBC domain is nearly always smaller than the
Rab Rab may refer to: Places * Rab (island), an island in Croatia * Rab (town), on the island of Rab * Ráb, the Slovak name of Győr, a city in Hungary * Rąb, a village in Poland People * Rab (surname), includes a list of people with the n ...
cohort in any individual
genome A genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding genes, other functional regions of the genome such as ...
, 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 betwee
RUTBC3
RabGAP-5 and
Rab5A Ras-related protein Rab-5A is a protein that in humans is encoded by the ''RAB5A'' gene. Function RAB5A localizes to early endosomes where it is involved in the recruitment of RAB7A and the maturation of these compartments to early endosomes. ...
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 Target may refer to: Warfare and shooting * Shooting target, used in marksmanship training and various shooting sports ** Bullseye (target), the goal one for which one aims in many of these sports ** Aiming point, in field artille ...
of TBC proteins. However, there has been a second approach to identifying the target Rabs of TBC by investigating their ''
in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
'' 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 vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
''. In addition, research has shown that TBC proteins are associated with some human
disease A disease is a particular abnormal condition that adversely affects the structure or function (biology), function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical condi ...
s. For example, a dysfunction of
TBC1D1 TBC1 domain family member 1 is a protein that in humans is encoded by the ''TBC1D1'' gene. TBC1D1 is the founding member of a family of proteins sharing a 180- to 200-amino acid TBC domain presumed to have a role in regulating cell growth and cel ...
and TBC1D4 directly affects
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
actions and
glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
uptake. Causing
overweight Being overweight is having more body fat than is optimally healthy. Being overweight is especially common where food supplies are plentiful and lifestyles are sedentary. , excess weight reached epidemic proportions globally, with more than ...
or leanness due to the fact that this two family members of TBC regulate insulin-stimulated GLUT4 translocation to the
plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
in
mammals A mammal () is a vertebrate animal of the class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three middle e ...
. Furthermore, many of them have been shown to be associated with
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
, 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.


References


External links

* * * * * * * * * * *{{cite journal , vauthors=Lamarche N, Hall A , title=GAPs for rho-related GTPases , journal=Trends in Genetics , volume=10 , issue=12 , pages=436–40 , year=1994 , pmid=7871593 , doi=10.1016/0168-9525(94)90114-7 Protein domains