Lipocalin

The lipocalins are a family of proteins which transport small hydrophobic molecules such as steroids, bilins, retinoids, and lipids. They share limited regions of sequence homology and a common tertiary structure architecture^{[1][2][3][4][5]}. This is an eight stranded antiparallel beta-barrel with a repeated + 1 topology enclosing a internal ligand binding site^[4][3].

These proteins are found in gram negative bacteria, vertebrate cells, and invertebrate cells, and in plants. Lipocalins have been associated with many biological processes, among them immune response, pheromone transport, biological prostaglandin synthesis, retinoid binding, and cancer cell interactions.

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Function

Immune Response

Lipocalin proteins are involved in inflammation 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. Human allergenic reactions to lipocalins have not been extensively investigated.

Pheromone Transport

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 nasal mucus of rodents, as well as mouse and rat urine.

Prostaglandin Synthesis

Main article: Prostaglandin

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

Retinoid Binding

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.

Cancer Cell Interactions

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 tumor protease 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 ^[6]. 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, Equ c 1 and Equ c 2.

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. Lipocalins have desirable properties in terms of crystallization ability, molecular size, and commercial availability. Structure determination involves such processes as crystallization and multi-dimensional Nuclear Magnetic Resonance spectroscopy (NMR). Specifically, this NMR technique is known as NOESY (Nuclear Overhauser Effect Spectroscopy), and is used to determine structures of otherwise complex macromolecules such as proteins. If lipocalins are genetically engineered in the attempt to modify their binding properties, they are called Anticalins.

Proteins included in the family

The name 'lipocalin' has been proposed^[1] for this protein family, but cytosolic fatty acid binding proteins are also included. The sequences of most members of the family, the core or kernal lipocalins, are characterised by three short conserved stretches of residues, while others, the outlier lipocalin group, share only one or two of these^[7][4]. Proteins known to belong to this family include alpha-1-microglobulin (protein HC); alpha-1-acid glycoprotein (orosomucoid)^[8]; aphrodisin; apolipoprotein D; beta-lactoglobulin; complement component C8 gamma chain^[9]; crustacyanin^[10]; epididymal-retinoic acid binding protein (E-RABP)^[11]; insectacyanin; odorant-binding protein (OBP); human pregnancy-associated endometrial alpha-2 globulin; probasin (PB), a prostatic protein; prostaglandin D synthase (EC 5.3.99.2)^[12]; purpurin; Von Ebner's gland protein (VEGP)^[13]; and lizard epididymal secretory protein IV (LESP IV)^[14].

Human proteins that contain lipocalin domain

AMBP; APOD; C8G; CRABP1; CRABP2; FABP1; FABP2; FABP3; FABP4; FABP5; FABP6; FABP7; LCN1; LCN10; LCN12; LCN2; LCN8; LCN9; OBP2A; OBP2B; ORM1; ORM2; PAEP; PERF15; PMP2; PTGDS; RBP1; RBP2; RBP4; RBP5; RBP7; UNQ2541;

References

Further reading

• The Lipocalins: A Review. The Edward Jenner Institute for Vaccine Research.
• Virtanen, Tuomas et al. "Important Animal Allergens Are Lipocalin Proteins: Why Are They Allergenic?" Department of Clinical Microbiology; University of Kuopio. International Archives of Allergy and Immunology, 1999.
• Bratt, T. "Lipocalins and Cancer". M&E Biotech. PubMed; 10/18/2000.
• Charron, Jean-Benoit Frenette et al. "Identification, Expression, and Evolutionary Analyses of Plant Lipocalins" Département des Sciences Biologiques, Université du Québec à Montréal. 10/04/2005.
• Novotny, M.V. et al. "Pheromones, binding proteins and receptor responses in rodents" Institute for Pheromone Research, University of Indiana, Bloomington. Biochemical Society Transactions, 2003.
• Diwan, J. "Review: Protein Structure". Rensselaer Polytechnic Institute. 2003.

See also

Retinol binding protein

This article includes text from the public domain Pfam and InterPro IPR000566