Lipocalin
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The lipocalins are a family of proteins which transport small hydrophobic molecules such as steroids, bilins, retinoids, and
lipids Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
and most lipocalins are also able to bind to complexed iron (via
siderophore Siderophores (Greek: "iron carrier") are small, high-affinity iron- chelating compounds that are secreted by microorganisms such as bacteria and fungi. They help the organism accumulate iron. Although a widening range of siderophore functions is n ...
s or flavonoids) as well as
heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consis ...
. They share limited regions of sequence homology and a common tertiary structure architecture. This is an eight stranded antiparallel
beta barrel In protein structures, a beta barrel is a beta sheet composed of tandem repeats that twists and coils to form a closed toroidal structure in which the first strand is bonded to the last strand (hydrogen bond). Beta-strands in many beta-barrels are ...
with a repeated + 1 topology enclosing an internal ligand binding site. These proteins are found in
gram negative The gram (originally gramme; SI unit symbol g) is a unit of mass in the International System of Units (SI) equal to one one thousandth of a kilogram. Originally defined as of 1795 as "the absolute weight of a volume of pure water equal to th ...
bacteria,
vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
cells, and
invertebrate Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...
cells, and in plants. Lipocalins have been associated with many biological processes, among them
immune In biology, immunity is the capability of multicellular organisms to resist harmful microorganisms. Immunity involves both specific and nonspecific components. The nonspecific components act as barriers or eliminators of a wide range of pathogens ...
response,
pheromone A pheromone () is a secreted or excreted chemical factor that triggers a social response in members of the same species. Pheromones are chemicals capable of acting like hormones outside the body of the secreting individual, to affect the behavio ...
transport, biological prostaglandin synthesis, retinoid binding, and
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
cell interactions.


Function


Immune response

Lipocalin proteins are important key players of nutritional immunity by withholding and sequestering micronutrients. They are thereby able to regulate inflammatory and
detoxification Detoxification or detoxication (detox for short) is the physiological or medicinal removal of toxic substances from a living organism, including the human body, which is mainly carried out by the liver. Additionally, it can refer to the period of ...
processes caused by immune system activation in mammals. They are known respiratory
allergen An allergen is a type of antigen that produces an abnormally vigorous immune response in which the immune system fights off a perceived threat that would otherwise be harmless to the body. Such reactions are called allergies. In technical terms ...
s of mice, cats, dogs, horses, and other animals. Examples of lipocalin proteins involved in immune system responses include
alpha-1-microglobulin Alpha-1-microglobulin (A1M, α1-microglobulin,B. Ekström, P.A. Peterson, I. Berggård "A urinary and plasma alpha-1-glycoprotein of low molecular weight: isolation and some properties." ''Biochem. Biophys. Res. Commun'' 1975, vol. sometimes also ca ...
, alpha-1-acid glycoprotein, an
C8gamma
Structural information for many immune system influencing lipocalin proteins is available, while their exact role in biological systems is still somewhat unclear. Lipocalin allergens have been shown to evoke a Th2-deviated immune response, important for allergic sensitization, when applied in their apo-form (with an empty calyx devoid of ligands), whereas the holo-form seemed to exert immune-suppressive properties ''in vitro''.


Pheromone transport

The lipocalin family has been connected with the transport of mammalian
pheromones A pheromone () is a secreted or excreted chemical factor that triggers a social response in members of the same species. Pheromones are chemicals capable of acting like hormones outside the body of the secreting individual, to affect the behavio ...
due to easily observable protein-pheromone interactions. Lipocalins are comparatively small in size, and are thus less complicated to study as opposed to large, bulky proteins. They can also bind to various ligands for different biological purposes. Lipocalins have been detected as carrier proteins of important pheromones in the nasal
mucus Mucus ( ) is a slippery aqueous secretion produced by, and covering, mucous membranes. It is typically produced from cells found in mucous glands, although it may also originate from mixed glands, which contain both serous and mucous cells. It ...
of rodents.
Major urinary proteins Major urinary proteins (Mups), also known as α2u-globulins, are a subfamily of proteins found in abundance in the urine and other secretions of many animals. Mups provide a small range of identifying information about the donor animal, when dete ...
, a lipocalin subfamily, are found in mouse and rat urine and may act as protein pheromones themselves. *


Prostaglandin synthesis

This family of proteins plays a part in the biological system of terminal prostaglandin synthesis.


Retinoid binding

Retinol Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family found in food and used as a dietary supplement. As a supplement it is used to treat and prevent vitamin A deficiency, especially that which results in xeroph ...
, (vitamin A), is an important micronutrient that affects eyesight, cell differentiation, immune system function, bone growth, and
tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
suppression. Retinol absorption and metabolism depends on lipocalins that act as binding proteins. Retinyl
esters In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
(present in meats) and beta-carotene (present in plants) are the two main sources of retinoids in the diet. After intake, they are converted to retinol, successively metabolized, and finally bound to retinol binding proteins (lipocalins) in the
blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intr ...
.


Cancer cell interactions

Because lipocalins are
extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
proteins, their
intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
effects are not obvious, and demand further study. However,
lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...
ligands, present as substituents to the lipocalins, have the ability to enter the cell, where they can act as
tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
inhibitors. This research suggests another possible route of protein-tumor investigations.


Allergens

Some of the proteins in this family are allergens. Allergies are hypersensitivity reactions of the immune system to specific substances called allergens (such as pollen, stings, drugs, or food) that, in most people, result in no symptoms. A nomenclature system has been established for antigens (allergens) that cause IgE-mediated atopic allergies in humans. HO/IUIS Allergen Nomenclature Subcommittee King T.P., Hoffmann D., Loewenstein H., Marsh D.G., Platts-Mills T.A.E., Thomas W. Bull. World Health Organ. 72:797-806(1994)/ref> This nomenclature system is defined by a designation that is composed of the first three letters of the genus; a space; the first letter of the species name; a space and an Arabic number. In the event that two species names have identical designations, they are discriminated from one another by adding one or more letters (as necessary) to each species designation. The allergens in this family include allergens with the following designations: Bla g 4, Bos d 2, Bos d 5, Can f 1, Can f 2, Fel d 4, Equ c 1 and Equ c 2.


Hormone

LCN2 (Lipocalin 2) acts as bone-derived hormone which crosses the BBB and acts on PVN paraventricular nucleus of hypothalamus in the brain.


Structure

Although lipocalins are a broad family of greatly varied proteins, their three-dimensional structure is a unifying characteristic. Lipocalins have an eight-stranded, antiparallel, symmetrical β-barrel fold, which is, in essence, a beta sheet which has been rolled into a cylindrical shape. Inside this barrel is located a ligand binding site, which plays an important role in the lipocalin classification as a transport protein. If lipocalins are genetically engineered in the attempt to modify their binding properties, they are called
anticalin Anticalin proteins are artificial proteins that are able to bind to antigens, either to proteins or to small molecules. They are not structurally related to antibodies, which makes them a type of antibody mimetic. Instead, they are derived from h ...
s.


Family members

The name "lipocalin" has been proposed for this protein family, but
cytosolic The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
fatty acid binding protein The fatty-acid-binding proteins (FABPs) are a family of transport proteins for fatty acids and other lipophilic substances such as eicosanoids and retinoids. These proteins are thought to facilitate the transfer of fatty acids between extra- and ...
s are also included. The sequences of most members of the family, the core or kernel lipocalins, are characterised by three short conserved stretches of residues, while others, the outlier lipocalin group, share only one or two of these. Proteins known to belong to this family include
alpha-1-microglobulin Alpha-1-microglobulin (A1M, α1-microglobulin,B. Ekström, P.A. Peterson, I. Berggård "A urinary and plasma alpha-1-glycoprotein of low molecular weight: isolation and some properties." ''Biochem. Biophys. Res. Commun'' 1975, vol. sometimes also ca ...
(protein HC);
major urinary proteins Major urinary proteins (Mups), also known as α2u-globulins, are a subfamily of proteins found in abundance in the urine and other secretions of many animals. Mups provide a small range of identifying information about the donor animal, when dete ...
; alpha-1-acid glycoprotein (
orosomucoid Orosomucoid (ORM) or alpha-1-acid glycoprotein (''α1AGp'', ''AGP'' or ''AAG'') is an acute phase protein found in plasma. It is an alpha-globulin glycoprotein and is modulated by two polymorphic genes. It is synthesized primarily in hepatoc ...
); aphrodisin;
apolipoprotein D Apolipoprotein D (ApoD) is a protein that in humans is encoded by the ''APOD'' gene. Unlike other lipoproteins, which are mainly produced in the liver, apolipoprotein D is mainly produced in the brain and testes. It is a 29 kDa glycoprotein disco ...
;
beta-lactoglobulin β-Lactoglobulin (BLG) is the major whey protein of cow and sheep's milk (~3 g/L), and is also present in many other mammalian species; a notable exception being humans. Its structure, properties and biological role have been reviewed many time ...
; complement component C8 gamma chain;
crustacyanin Crustacyanin is a carotenoprotein biological pigment found in the exoskeleton of lobsters and responsible for their blue colour. β-Crustacyanin (β-CR), is composed of two stacked astaxanthin carotenoids that absorb at λ = 580–590 nm (2. ...
; epididymal-retinoic acid binding protein (E-RABP); insectacyanin;
odorant binding protein Odorant-binding proteins (OBPs) are small (10 to 30 kDa) soluble proteins secreted by auxiliary cells surrounding olfactory receptor neurons, including the nasal mucus of many vertebrate species and in the sensillar lymph of chemosensory sensilla o ...
(OBP); human pregnancy-associated endometrial alpha-2 globulin (
PAEP Glycodelin (GD) also known as human placental protein-14 (PP-14) progestogen-associated endometrial protein (PAEP) or pregnancy-associated endometrial alpha-2 globulin is a glycoprotein that inhibits cell immune function and plays an essential ...
); probasin (PB), a prostatic protein; prostaglandin D synthase; purpurin; Von Ebner's gland protein ( VEGP); and lizard epididymal secretory protein IV (LESP IV). Human proteins that contain lipocalin domain include: * AMBP,
APOD Astronomy Picture of the Day (APOD) is a website provided by NASA and Michigan Technological University (MTU). According to the website, "Each day a different image or photograph of our universe is featured, along with a brief explanation written ...
* C8G,
CRABP1 Cellular retinoic acid-binding protein 1 is a protein that in humans is encoded by the ''CRABP1'' gene. CRABP1 is assumed to play an important role in retinoic acid-mediated differentiation and proliferation processes. It is structurally simila ...
,
CRABP2 Cellular retinoic acid-binding protein 2 is a cytoplasmic binding protein that in humans is encoded by the ''CRABP2'' gene. CRABP2 is structurally similar to CRABP1, but CRABP2 has a lower affinity for retinoic acid (RA). CRABP2 is associated wit ...
*
FABP1 ''FABP1'' is a human gene coding for the protein product FABP1 (Fatty Acid-Binding Protein 1). It is also frequently known as liver-type fatty acid-binding protein (LFABP). FABP1 is primarily expressed in the liver where it is involved in the bi ...
,
FABP2 Fatty acid-binding protein 2 (FABP2) also known as Intestinal-type fatty acid-binding protein (I-FABP) is a protein that in humans is encoded by the ''FABP2'' gene. Function The intracellular fatty acid-binding proteins (FABPs) belong to a mul ...
,
FABP3 Heart-type fatty acid binding protein (hFABP) also known as mammary-derived growth inhibitor is a protein that in humans is encoded by the ''FABP3'' gene. Function Heart-type Fatty Acid-Binding Protein (H-FABP) is a small cytoplasmic protein ( ...
, FABP4,
FABP5 Fatty acid-binding protein, epidermal is a protein that in humans is encoded by the ''FABP5'' gene. Function This gene encodes the fatty acid binding protein found in epidermal cells, and was first identified as being upregulated in psoriasis ...
, FABP6,
FABP7 Fatty acid binding protein 7, brain (FABP7; also brain lipid binding protein, BLBP), is a human gene. Function The protein encoded by this gene is a brain fatty acid binding protein. Fatty acid binding proteins (FABPs) are a family of small, h ...
*
LCN1 Lipocalin-1 is a protein that in humans is encoded by the ''LCN1'' gene. The protein encoded by this gene belongs to the lipocalin family. Lipocalins are a group of extracellular proteins that are able to bind lipophiles by enclosure within their ...
,
LCN2 Lipocalin-2 (LCN2), also known as oncogene 24p3 or neutrophil gelatinase-associated lipocalin (NGAL), is a protein that in Human, humans is encoded by the ''LCN2'' gene. NGAL is involved in innate immunity by sequestering iron and preventing its ...
, LCN8, LCN9, LCN10, LCN12 * OBP2A, OBP2B *
ORM1 Alpha-1-acid glycoprotein 1 is a protein that in humans is encoded by the ''ORM1'' gene. This gene encodes a key acute phase plasma protein. Because of its increase due to acute inflammation, this protein is classified as an acute-phase reactant ...
, ORM2 *
PAEP Glycodelin (GD) also known as human placental protein-14 (PP-14) progestogen-associated endometrial protein (PAEP) or pregnancy-associated endometrial alpha-2 globulin is a glycoprotein that inhibits cell immune function and plays an essential ...
, PERF15, PMP2, PTGDS *
RBP1 Retinol binding protein 1, cellular, also known as RBP1, is a protein that in humans is encoded by the ''RBP1'' gene. Function RBP1 is the carrier protein involved in the transport of retinol (vitamin A alcohol) from the liver storage site to p ...
,
RBP2 Retinol-binding protein 2 (RBP2) is a protein that in humans is encoded by the ''RBP2'' gene. Function RBP2 is an abundant protein present in the small intestinal epithelium. It is thought to participate in the uptake and/or intracellular meta ...
, RBP4, RBP5, RBP7 * UNQ2541


See also

*
Retinol binding protein Retinol-binding proteins (RBP) are a family of proteins with diverse functions. They are carrier proteins that bind retinol. Assessment of retinol-binding protein is used to determine visceral protein mass in health-related nutritional studies. R ...


References


Further reading

* * * * *


External links


Lipocalins in SCOP database
* - Calculated spatial positions of some Lipocalins in membranes {{InterPro content, IPR000566 Protein families