The asialoglycoprotein receptors (ASGPR) are

lectin Lectins are carbohydrate-binding proteins that are highly specific for sugar groups that are part of other molecules, so cause agglutination of particular cells or precipitation of glycoconjugates and polysaccharides. Lectins have a role in rec ...

s which bind

asialoglycoprotein If terminal sialic acid residues are removed from glycoproteins, the resulting proteins are known as asialoglycoproteins. The exposure of the subterminal galactose residues results in rapid clearance of the glycoproteins from the circulation th ...

and

glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...

s from which a

sialic acid Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone. The term "sialic acid" (from the Greek for saliva, - ''síalon'') was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this gr ...

has been removed to expose

galactose Galactose (, '' galacto-'' + '' -ose'', "milk sugar"), sometimes abbreviated Gal, is a monosaccharide sugar that is about as sweet as glucose, and about 65% as sweet as sucrose. It is an aldohexose and a C-4 epimer of glucose. A galactose molec ...

residues. The receptors, which are

integral membrane proteins An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a signi ...

and are located on mammalian hepatocytes (

liver cell A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein biosynthesis, Protein synthesis * Storage protein, Protein storage * Transformation of carboh ...

s), remove target glycoproteins from circulation. The asialoglycoprotein receptor has been demonstrated to have high expression on the surface of

hepatocytes A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, b ...

s, several human

carcinoma Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesodermal ...

cell line An immortalised cell line is a population of cells from a multicellular organism which would normally not proliferate indefinitely but, due to mutation, have evaded normal cellular senescence and instead can keep undergoing division. The cell ...

s It is also weakly expressed by glandular cells of the gallbladder ] and the stomach. Lactobionic acid has been used as a targeting moiety for

drug delivery Drug delivery refers to approaches, formulations, manufacturing techniques, storage systems, and technologies involved in transporting a pharmaceutical compound to its target site to achieve a desired therapeutic effect. Principles related to d ...

to cells expressing asialoglycoprotein receptors. The asialoglycoprotein receptor contains two subunits, asialoglycoprotein receptor 1 (ASGR1) and asialoglycoprotein receptor 2 (ASGR2). These subunits may form different quaternary forms such as dimers, trimers, tetramers to allow for specific substrate binding or endocytosis. ASGR 1 is the major subunit and has 8 exons and is roughly 6 kb in length. ASGR 2 is the minor subunit and has 9 exons and is about 13.5 kb long.

History

The asialoglycoprotein receptor was first characterized in 1968 b
Morell et al.
and was the first mammalian lectin identified. The researchers transferred radioactively-labeled

ceruloplasmin Ceruloplasmin (or caeruloplasmin) is a ferroxidase enzyme that in humans is encoded by the ''CP'' gene. Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 194 ...

that had undergone a reaction via the enzyme

neuraminidase Exo-α-sialidase (EC 3.2.1.18, sialidase, neuraminidase; systematic name acetylneuraminyl hydrolase) is a glycoside hydrolase that cleaves the glycosidic linkages of neuraminic acids: : Hydrolysis of α-(2→3)-, α-(2→6)-, α-(2→8)- glycos ...

to remove the protein's terminal

, generating an

. Upon injection of the radioactive protein into rabbits, the radioactivity of the entire asialoglycoprotein (rather than a portion of the protein) quickly moved from the blood into the liver. This rapid movement from the blood into the liver only occurred if the sialic acid of the protein was removed; i.e., if the protein had an exposed galactose residue (that would normally be covered by the sialic acid). Thus, it was concluded that a receptor is capable of recognizing asialoglycoproteins (i.e., proteins that have lost their terminal sialic acids) and removing them from circulation by transporting them to the liver.

Function

Asialoglycoprotein receptors function to catabolize galactosyl and N-acetylgalactosaminyl-containing substrates. More specifically, in most mammals, the asialoglycoprotein receptor removes

glycoproteins Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...

that have had some of their sugars, particularly a terminal

, removed from the end of the protein.

Mechanism of action

The human asialoglycoprotein receptors composed of two units, H1 and H2. Each of these units have their N-terminus within the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

of a liver cell, and a carbohydrate recognition domain (CRD) on the extracellular side. The CRD functions to bind to asialoglycoproteins through a calcium ion-mediated interaction. In particular, the hydroxyl groups of the terminal sugars (usually

) of the asialoglycoprotein form hydrogen bonds with the CRD of the asialoglycoprotein receptor; proper positioning and facilitation of these hydrogen bonds is caused by the presence of Ca2+.

Affinity of ASGPR to ASGP

The affinity of the ASGPR-ASGP interaction is dependent on factors including the number of sugars present on the ASGP. For example, ASGPs with a one galactose have a higher

dissociation constant In chemistry, biochemistry, and pharmacology, a dissociation constant (K_D) is a specific type of equilibrium constant that measures the propensity of a larger object to separate (dissociate) reversibly into smaller components, as when a complex fa ...

(i.e., a lower affinity interaction) compared an ASGPR with several sugars attached. This increased affinity in the presence of more sugars is likely due to the formation of more interactions between the carbohydrate recognition domain of the ASGPR and the sugars on the ASGP. The affinity of the interaction is also mediated by the modifications of the terminal galactose; for example, ASGPs with N-acetylgalactosamine have a higher affinity interaction for the ASGPR compared to ASGPs with a galactose.

References

External links

* C-type lectins {{Transmembrane receptors