CBS domain
Encyclopedia
The CBS domain is a protein domain
found in a range of proteins in all species from bacteria to man. It was first identified as a conserved sequence
region in 1997 and named after cystathionine beta synthase
, one of the proteins it is found in. CBS domains are also found in a wide variety of other proteins such as inosine monophosphate dehydrogenase, voltage gated chloride channels
and AMP-activated protein kinase
(AMPK). CBS domains regulate the activity of associated enzymatic and transporter domains in response to binding molecules with adenosyl groups such as AMP
and ATP
, or s-adenosylmethionine.
pattern that is folded
into a globular tertiary structure
that contains a three-stranded antiparallel β-sheet
with two α-helices
on one side. CBS domains are always found in pairs in protein sequences and each pair of these domains tightly associate in a pseudo dimeric arrangement through their β-sheets forming a so-called CBS-pair or Bateman domain. These CBS domain pairs can associate in a head-to-head (i.e. PDB codes, , ) or a head-to-tail (i.e. PDB codes ) manner forming a disk-like compact structure. By doing so, they form clefts that constitute the canonical ligand binding regions. In principle, the number of canonical binding sites matches the number of CBS domains within the molecule and are traditionally numbered according to the CBS domain that contains each of the conserved aspartate residues that potentially interact with the ribose of the nucleotides. However, not all of these cavities might necessarily bind nucleotides or be functional. Recently, a non-canonical site for AMP have also been described in protein MJ1225 from M. jannaschii, though its functional role is still unknown.
and ATP
, or s-adenosylmethionine, but they may also bind metallic ions such as Mg2+. Upon binding these different ligands the CBS domains regulate the activity of associated enzymatic domains. The molecular mechanisms underlying this regulation are just starting to be elucidated. At the moment, two different type of mechanisms have been proposed. The first one claims that the nucleotide portion of the ligand induces essentially no change in the protein structure, the electrostatic potential at the binding site being the most significant property of adenosine nucleotide binding. This "static" response would be involved in processes in which regulation by energy charge would be advantageous. On the contrary, the second type of mechanism (denoted as "dynamic") involves dramatic conformational changes in the protein structure upon ligand binding and has been reported for the cytosolic domain of the Mg2+ transporter MgtE from Thermus thermophilus
, the unknown function protein MJ0100 from M. jannaschii and the regulatory region of Clostridium perfringens
pyrophosphatase.
, membrane transporters or DNA-binding domains. However, proteins that contain only CBS domains are also often found, particularly in prokaryotes. These standalone CBS domain proteins might form complexes upon binding to other proteins such as kinases to which they interact with and regulate.
.
Humans have a number of voltage gated chloride channel genes and mutations in the CBS domains of several of these have been identified as the cause of genetic diseases. Mutations in CLCN1
lead to Myotonia
, mutations in CLCN2
can lead to Idiopathic generalised epilepsy
, mutations in CLCN5
can lead to Dent's disease
, mutations in CLCN7
can lead to Osteopetrosis
and mutations in CLC-Kb can lead to Bartter syndrome
.
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
found in a range of proteins in all species from bacteria to man. It was first identified as a conserved sequence
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
region in 1997 and named after cystathionine beta synthase
Cystathionine beta synthase
Cystathionine-β-synthase, also known as CBS, is an enzyme that in humans is encoded by the CBS gene. It catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine:...
, one of the proteins it is found in. CBS domains are also found in a wide variety of other proteins such as inosine monophosphate dehydrogenase, voltage gated chloride channels
Chloride channel
Chloride channels are a superfamily of poorly understood ion channels consisting of approximately 13 members.Chloride channels display a variety of important physiological and cellular roles that include regulation of pH, volume homeostasis, organic solute transport, cell migration, cell...
and AMP-activated protein kinase
AMP-activated protein kinase
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis. It consists of three proteins that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of...
(AMPK). CBS domains regulate the activity of associated enzymatic and transporter domains in response to binding molecules with adenosyl groups such as AMP
Adenosine monophosphate
Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
and ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
, or s-adenosylmethionine.
Structure
The CBS domain is composed of a beta-alpha-beta-beta-alpha secondary structureSecondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
pattern that is folded
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
into a globular tertiary structure
Tertiary structure
In biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
that contains a three-stranded antiparallel β-sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
with two α-helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
on one side. CBS domains are always found in pairs in protein sequences and each pair of these domains tightly associate in a pseudo dimeric arrangement through their β-sheets forming a so-called CBS-pair or Bateman domain. These CBS domain pairs can associate in a head-to-head (i.e. PDB codes, , ) or a head-to-tail (i.e. PDB codes ) manner forming a disk-like compact structure. By doing so, they form clefts that constitute the canonical ligand binding regions. In principle, the number of canonical binding sites matches the number of CBS domains within the molecule and are traditionally numbered according to the CBS domain that contains each of the conserved aspartate residues that potentially interact with the ribose of the nucleotides. However, not all of these cavities might necessarily bind nucleotides or be functional. Recently, a non-canonical site for AMP have also been described in protein MJ1225 from M. jannaschii, though its functional role is still unknown.
Ligand binding
It has been shown that CBS domains bind to adenosyl groups in molecules such as AMPAdenosine monophosphate
Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
and ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
, or s-adenosylmethionine, but they may also bind metallic ions such as Mg2+. Upon binding these different ligands the CBS domains regulate the activity of associated enzymatic domains. The molecular mechanisms underlying this regulation are just starting to be elucidated. At the moment, two different type of mechanisms have been proposed. The first one claims that the nucleotide portion of the ligand induces essentially no change in the protein structure, the electrostatic potential at the binding site being the most significant property of adenosine nucleotide binding. This "static" response would be involved in processes in which regulation by energy charge would be advantageous. On the contrary, the second type of mechanism (denoted as "dynamic") involves dramatic conformational changes in the protein structure upon ligand binding and has been reported for the cytosolic domain of the Mg2+ transporter MgtE from Thermus thermophilus
Thermus thermophilus
Thermus thermophilus is a Gram negative eubacterium used in a range of biotechnological applications, including as a model organism for genetic manipulation, structural genomics, and systems biology. The bacterium is extremely thermophilic, with an optimal growth temperature of about...
, the unknown function protein MJ0100 from M. jannaschii and the regulatory region of Clostridium perfringens
Clostridium perfringens
Clostridium perfringens is a Gram-positive, rod-shaped, anaerobic, spore-forming bacterium of the genus Clostridium. C. perfringens is ever present in nature and can be found as a normal component of decaying vegetation, marine sediment, the intestinal tract of humans and other vertebrates,...
pyrophosphatase.
Associated domains
CBS domains are often found in proteins that contain other domains. These domains are usually enzymaticEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
, membrane transporters or DNA-binding domains. However, proteins that contain only CBS domains are also often found, particularly in prokaryotes. These standalone CBS domain proteins might form complexes upon binding to other proteins such as kinases to which they interact with and regulate.
Mutations leading to disease
Mutations in some human CBS domain containing proteins leads to genetic diseases. For example mutations in the Cystathionine-beta-synthase protein lead to an inherited disorder of the metabolism called homocystinuria . Mutations in the gamma subunit of the AMPK enzyme have been shown to lead to Familial hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome . Mutations in the CBS domains of the IMPDH enzyme lead to the eye condition Retinitis pigmentosaRetinitis pigmentosa
Retinitis pigmentosa is a group of genetic eye conditions that leads to incurable blindness. In the progression of symptoms for RP, night blindness generally precedes tunnel vision by years or even decades. Many people with RP do not become legally blind until their 40s or 50s and retain some...
.
Humans have a number of voltage gated chloride channel genes and mutations in the CBS domains of several of these have been identified as the cause of genetic diseases. Mutations in CLCN1
CLCN1
Chloride channel protein, skeletal muscle is a protein that in humans is encoded by the CLCN1 gene. Mutations in this protein cause congenital myotonia....
lead to Myotonia
Myotonia
Myotonia is a symptom of a small handful of certain neuromuscular disorders characterized by the slow relaxation of the muscles after voluntary contraction or electrical stimulation. Generally, repeated effort is needed to relax the muscles, and the condition improves after the muscles have warmed...
, mutations in CLCN2
CLCN2
Chloride channel protein 2 is a protein that in humans is encoded by the CLCN2 gene. Mutations of this gene have been found to cause Idiopathic generalised epilepsy . CLCN2 contains a transmembrane region that is involved in chloride ion transport as well two intracellular copies of the CBS domain....
can lead to Idiopathic generalised epilepsy
Generalised epilepsy
Generalised epilepsy, also known as primary generalised epilepsy or idiopathic epilepsy, is a form of epilepsy characterised by generalised seizures with no apparent cause...
, mutations in CLCN5
CLCN5
H/Cl exchange transporter 5 is a protein that in humans is encoded by the CLCN5 gene.- External links :...
can lead to Dent's disease
Dent's disease
Dent's disease is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, hypercalciuria, calcium nephrolithiasis, nephrocalcinosis and chronic renal failure."Dent's...
, mutations in CLCN7
CLCN7
Chloride channel 7, also known as CLCN7, is a human gene. In melanocytic cells this gene is regulated by the Microphthalmia-associated transcription factor.-External Links:*...
can lead to Osteopetrosis
Osteopetrosis
Osteopetrosis, literally "stone bone", also known as marble bone disease and Albers-Schonberg disease is an extremely rare inherited disorder whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which the bones become less dense and more brittle,...
and mutations in CLC-Kb can lead to Bartter syndrome
Bartter syndrome
Bartter syndrome is a rare inherited defect in the thick ascending limb of the loop of Henle. It is characterized by low potassium levels , increased blood pH , and normal to low blood pressure. There are two types of Bartter syndrome: neonatal and classic...
.