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Calbindins are three different
calcium-binding protein Calcium-binding proteins are proteins that participate in calcium cell signalling pathways by binding to Ca2+, the calcium ion that plays an important role in many cellular processes. Calcium-binding proteins have specific domains that bind to ca ...
s: calbindin,
calretinin Calretinin, also known as calbindin 2 (formerly 29 kDa calbindin), is a calcium-binding protein involved in calcium signaling. In humans, the calretinin protein is encoded by the ''CALB2'' gene. Function This gene encodes an intracellular c ...
and
S100G S100 calcium-binding protein G (S100G) is a protein that in humans is encoded by the ''S100G'' gene. This gene encodes calbindin Calbindins are three different calcium-binding proteins: calbindin, calretinin and S100G. They were originall ...
. They were originally described as vitamin D-dependent calcium-binding proteins in the intestine and kidney in the chick and mammals. They are now classified in different
subfamilies In biological classification, a subfamily (Latin: ', plural ') is an auxiliary (intermediate) taxonomic rank, next below family but more inclusive than genus. Standard nomenclature rules end subfamily botanical names with "-oideae", and zool ...
as they differ in the number of Ca2+ binding
EF hand The EF hand is a helix–loop–helix structural domain or ''motif'' found in a large family of calcium-binding proteins. The EF-hand motif contains a helix–loop–helix topology, much like the spread thumb and forefinger of the human hand, i ...
s.


Calbindin 1

Calbindin 1 or simply calbindin was first shown to be present in the intestine in birds and then found in the mammalian kidney. It is also expressed in a number of neuronal and endocrine cells, particularly in the
cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebe ...
. It is a 28 kDa protein encoded in humans by the ''CALB1'' gene. Calbindin contains 4 active calcium-binding
domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined ** Domain of definition of a partial function ** Natural domain of a partial function ** Domain of holomorphy of a function * ...
s, and 2 modified domains that have lost their calcium-binding capacity. Calbindin acts as a calcium buffer and calcium sensor and can hold four Ca2+ in the EF-hands of loops EF1, EF3, EF4 and EF5. The structure of rat calbindin was originally solved by nuclear magnetic resonance and was one of the largest proteins then to be determined by this technique. The sequence of calbindin is 263 residues in length and has only one chain. The sequence consists mostly of alpha helices but beta sheets are not absent. According to the NMR PDB (PDB entry 2G9B) it is 44% helical with 14 helices containing 117 residues, and 4% beta sheet with 9 strands containing 13 residues. In 2018 the X-ray crystal structure of human calbindin was published (PDB entry 6FIE). There were differences observed between the nuclear magnetic resonance and crystal structure despite 98% sequence identity between the rat and human isoforms. Small angle X-ray scattering indicates that the crystal structure better predicts the properties of calbindin in solution compared with the structure determined by nuclear magnetic resonance. Calbindin is a
vitamin D Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 ( ...
–responsive gene in many tissues, in particular the chick intestine, where it has a clear function in mediating calcium absorption. In the brain, its synthesis is independent of vitamin-D.


Calbindin 2 (Calretinin)

Calretinin, also known as calbindin 2, is a 29 kDa protein with 58% homology to calbindin 1 and principally found in nervous tissues. It is encoded in humans by the ''CALB2'' gene and was formerly known as calbindin-D29k.


Calbindin 3 (S100G)

S100G, formerly calbindin 3 and calbindin-D9k, is present in mammalian
enterocytes Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase i ...
(epithelial cells of the intestine). S100G can also be found in the kidney and
uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...
in some mammalian species. It is encoded in humans by the ''
S100G S100 calcium-binding protein G (S100G) is a protein that in humans is encoded by the ''S100G'' gene. This gene encodes calbindin Calbindins are three different calcium-binding proteins: calbindin, calretinin and S100G. They were originall ...
'' gene which has also been termed ''CALB3''. Nonetheless, there is no homology between calbindin 1 and S100G, apart from their calcium binding domains ( EF-hands): S100G has two EF-hands, and calbindin 1 has six. Unlike calbindin 1 and 2, S100G is a member of the S100 family of
calcium-binding proteins Calcium-binding proteins are proteins that participate in calcium cell signalling pathways by binding to Ca2+, the calcium ion that plays an important role in many cellular processes. Calcium-binding proteins have specific domains that bind to cal ...
. S100G mediates the transport of calcium across the enterocytes from the apical side, where entry is regulated by the
calcium channel A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, although there are also ligand-gated calcium channels. Comparison tables The following tables ex ...
TRPV6 TRPV6 is a membrane calcium (Ca2+) channel protein which is particularly involved in the first step in Ca2+absorption in the intestine. Classification Transient Receptor Potential Vanilloid subfamily member 6 (TRPV6) is an epithelial Ca2+ cha ...
, to the basolateral side, where
calcium pump Calcium pumps are a family of ion transporters found in the cell membrane of all animal cells. They are responsible for the active transport of calcium out of the cell for the maintenance of the steep Ca2+ electrochemical gradient across the cell m ...
s such as PMCA1 utilize intracellular
adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...
to pump calcium into the blood. The transport of calcium across the enterocyte cytoplasm appears to be rate-limiting for calcium absorption in the intestine; the presence of calbindin increases the amount of calcium crossing the cell without raising the free concentration. S100G may also stimulate the basolateral calcium-pumping
ATPase ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...
s.
Expression Expression may refer to: Linguistics * Expression (linguistics), a word, phrase, or sentence * Fixed expression, a form of words with a specific meaning * Idiom, a type of fixed expression * Metaphorical expression, a particular word, phrase, ...
of S100G, like that of calbindin 1, is stimulated by the active vitamin D
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
,
calcitriol Calcitriol is the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It is a hormone which binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the ...
although the precise mechanisms are still controversial. In mice in which the
vitamin D receptor The vitamin D receptor (VDR also known as the calcitriol receptor) is a member of the nuclear receptor family of transcription factors. Calcitriol (the active form of vitamin D, 1,25-(OH)2vitamin D3) binds to VDR, which then forms a heterodimer ...
is not expressed, S100G is less abundant, but not absent.


Discovery

Vitamin D-dependent calcium binding proteins were discovered in the cytosolic fractions of chicken
intestine The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans an ...
, and later in mammalian intestine and kidney, by researchers including Robert Wasserman of
Cornell University Cornell University is a private statutory land-grant research university based in Ithaca, New York. It is a member of the Ivy League. Founded in 1865 by Ezra Cornell and Andrew Dickson White, Cornell was founded with the intention to teac ...
. Such proteins bound
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...
in the micromolar range and were greatly reduced in
vitamin D Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 ( ...
-deficient animals. Expression could be induced by treating these animals with
vitamin D Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 ( ...
metabolites such as
calcitriol Calcitriol is the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It is a hormone which binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the ...
. They were found to exist in two distinct sizes with a
molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioche ...
of approximately 9 kDa and 28 kDa, and they were renamed calbindins.


References

{{Calcium-binding proteins Protein families