The lipocalins are a family of proteins which transport small hydrophobic molecules such as steroids, bilins, retinoids, and lipids, and most lipocalins are also able to bind to complexed iron (via siderophores[2] or flavonoids[3]) as well as heme.[4] They share limited regions of sequence homology and a common tertiary structure architecture.[5][6][7][8][9] This is an eight stranded antiparallel beta barrel with a repeated + 1 topology enclosing an internal ligand binding site.[7][8]
Lipocalin proteins are important key players of nutritional immunity by withholding and sequestering micronutrients.[11] They are thereby able to regulate inflammatory and detoxification processes caused by immune system activation in mammals. They are known respiratory allergens of mice, cats, dogs, horses, and other animals. Examples of lipocalin proteins involved in immune system responses include alpha-1-microglobulin, alpha-1-acid glycoprotein, and 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.[12]
The lipocalin family has been connected with the transport of mammalian pheromones 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 nasalmucus of rodents. Major urinary proteins, a lipocalin subfamily, are found in mouse and rat urine and may act as protein pheromones themselves.[13]
Retinol, (vitamin A), is an important micronutrient that affects eyesight, cell differentiation, immune system function, bone growth, and tumor suppression. Retinol absorption and metabolism depends on lipocalins that act as binding proteins. Retinyl esters (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.
Because lipocalins are extracellular proteins, their intracellular effects are not obvious, and demand further study. However, lipophilic ligands, present as substituents to the lipocalins, have the ability to enter the cell, where they can act as tumorprotease inhibitors. This research suggests another possible route of protein-tumor investigations.
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.[14] 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.[citation needed]
LCN2 (Lipocalin 2) acts as bone-derived hormone which crosses the BBB and acts on PVN paraventricular nucleus of hypothalamus in the brain.[citation needed]
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.[15] If lipocalins are genetically engineered in the attempt to modify their binding properties, they are called anticalins.[16]
^ abCowan SW, Newcomer ME, Jones TA (1990). "Crystallographic refinement of human serum retinol binding protein at 2A resolution". Proteins. 8 (1): 44–61. doi:10.1002/prot.340080108. PMID2217163. S2CID21613341.
^Godovac-Zimmermann J (February 1988). "The structural motif of beta-lactoglobulin and retinol-binding protein: a basic framework for binding and transport of small hydrophobic molecules?". Trends in Biochemical Sciences. 13 (2): 64–66. doi:10.1016/0968-0004(88)90031-X. PMID3238752.
^[WHO/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)]
^Flower DR, North AC, Attwood TK (October 1991). "Mouse oncogene protein 24p3 is a member of the lipocalin protein family". Biochemical and Biophysical Research Communications. 180 (1): 69–74. doi:10.1016/S0006-291X(05)81256-2. PMID1834059.
^Kremer JM, Wilting J, Janssen LH (March 1988). "Drug binding to human alpha-1-acid glycoprotein in health and disease". Pharmacological Reviews. 40 (1): 1–47. PMID3064105.
^Haefliger JA, Peitsch MC, Jenne DE, Tschopp J (1991). "Structural and functional characterization of complement C8 gamma, a member of the lipocalin protein family". Molecular Immunology. 28 (1–2): 123–131. doi:10.1016/0161-5890(91)90095-2. PMID1707134.
^Keen JN, Caceres I, Eliopoulos EE, Zagalsky PF, Findlay JB (April 1991). "Complete sequence and model for the A2 subunit of the carotenoid pigment complex, crustacyanin". European Journal of Biochemistry. 197 (2): 407–417. doi:10.1111/j.1432-1033.1991.tb15925.x. PMID2026162.
^Peitsch MC, Boguski MS (October 1991). "The first lipocalin with enzymatic activity". Trends in Biochemical Sciences. 16 (10): 363. doi:10.1016/0968-0004(91)90149-P. PMID1723819.
Paine K, Flower DR (October 2000). "The lipocalin website". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1482 (1–2): 351–352. doi:10.1016/S0167-4838(00)00166-7. PMID11058775.
Virtanen T, Zeiler T, Mäntyjärvi R (December 1999). "Important animal allergens are lipocalin proteins: why are they allergenic?". International Archives of Allergy and Immunology. 120 (4): 247–258. doi:10.1159/000024277. PMID10640908. S2CID1171463.
Bratt T (October 2000). "Lipocalins and cancer". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1482 (1–2): 318–326. doi:10.1016/S0167-4838(00)00154-0. PMID11058772.