Nutrition Guide

The ATPase activity of TAP is highly dependent on the presence of the correct substrate, and peptide binding is prerequisite for ATP hydrolysis. This prevents waste of ATP via peptide-independent hydrolysis.[6]

The specificity of TAP proteins was first investigated by trapping peptides in the ER using glycosylation. TAP binds to 8- to 16-residue peptides with equal affinity, while translocation is most efficient for peptides that are 8 to 12 residues long. Efficiency reduces for peptides longer than 12 residues.[8] However, peptides with more than 40 residues were translocated, albeit with low efficiency. Peptides with low affinity for the MHC class I molecule are transported out of the ER by an efficient ATP-dependent export protein. These outlined mechanisms may represent a mechanism for ensuring that only high-affinity peptides are bound to MHC class I.

TAP-mediated peptide transport is a multistep process. The peptide-binding pocket is formed by TAP-1 and TAP-2. Association with TAP is an ATP-independent event, ‘in a fast bimolecular association step, peptide binds to TAP, followed by a slow isomerisation of the TAP complex’.[5] It is suggested that the conformational change in structure triggers ATP hydrolysis and so initiates peptide transport.[6]

Both nucleotide-binding domains (NBDs) are required for peptide translocation, as each NBD cannot hydrolyse ATP alone. The exact mechanism of transport is not known; however, findings indicate that ATP binding to TAP-1 is the initial step in the transport process, and that ATP bound to TAP-1 induces ATP binding in TAP-2. It has also been shown that undocking of the loaded MHC class I is linked to the transport cycle of TAP caused by signals from the TAP-1 subunit.[7]

The TAP transporter is found in the ER lumen associated with the peptide-loading complex (PLC). This complex of ?2 microglobulin, calreticulin, ERp57, TAP, tapasin, and MHC class I acts to keep hold of MHC molecules until they have been fully loaded with peptides.[4]

Transporter associated with antigen processing (TAP) is a member of the ATP-binding-cassette transporter family.[1] It delivers cytosolic peptides into the endoplasmic reticulum (ER), where they bind to nascent MHC class I molecules.[2]

The TAP structure is formed of two proteins: TAP-1 and TAP-2, which have one hydrophobic region and one ATP-binding region each. They assemble into a heterodimer, which results in a four-domain transporter.[3]

ABC transporter transmembrane domain is main transmembrane structural unit of ATP-binding cassette transporter which consist of six transmembrane domaines. Many members of the ABC transporter family (Pfam PF00005) have two such regions.

Transporter 1, ATP-binding cassette, sub-family B (MDR/TAP), also known as TAP1, is a human gene.

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is involved in the pumping of degraded cytosolic peptides across the endoplasmic reticulum into the membrane-bound compartment where class I molecules assemble. Mutations in this gene may be associated with ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease.[1]

Mutations in both alleles of either ABCG5 or ABCG8 in the human results in sitosterolemia. Sitosterolemia (also known as phytosterolemia) is a rare autosomal recessively inherited lipid metabolic disorder characterized by the presence of tendon xanthomas, premature coronary artery disease and atherosclerotic disease, hemolytic episodes, arthralgias and arthritis. The hallmark of sitosterolemia is diagnostically elevated levels of plant sterols in the plasma.

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Under normal circumstances, a western diet contains almost equal amounts of cholesterol and noncholesterol sterols(such as plant sterols sitosterol, campesterol,and brassicasterol). However, only about 55% of total dietary cholesterol is absorbed and retained while almost none of the noncholesterol sterols are retained since the small amount of dietary non-cholesterols that do enter the body are rapidly excreted by the liver into bile, almost unchanged.

Sterolins are likely involved both in the selective transport of dietary cholesterol in and out of enterocytes and in selective sterol excretion by the liver into bile, as evidenced by the consequences when it is deficient or over expressed. The exact mechanism(s) whereby ABCG5/ABCG8 exert their effects on sterol metabolism has not yet been clarified. But it is suggested that the ABCG5/ABCG8 heterodimer shuttles cholesterol from the inner leaflet of the canalicular membrane through a chamber formed by the two half-transporters. Following ATP binding and hydrolysis, the complex undergoes a conformational change, flipping a cholesterol molecule into the outer membrane leaflet in a configuration that favors its release into the canalicular space.

Based on the clinical defects in sitosterolemia, ABCG5/ABCG8 are expressed in the liver and/or the intestine. 5 These genes respond to environmental dietary sterols, although whether they are also increased by high phytosterols has yet to determined.

It is worth to mention that other gene products play a role in dietary-cholesterol transport (such as ABCA1).

The molecular mechanisms regulating the absorption of dietary sterols in the body are poorly understood, and as sitosterolemia is a rare autosomal recessively inherited lipid metabolic disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols, studies have focused on the molecular basis of sitosterolemia to shed light on important principles concerning intestinal sterol absorption as well as cholesterol secretion into bile.

In 1998, sitosterolemia (STSL) locus has been mapped to the short arm of human chromosome 2 (2p21) after studying 10 well-characterized families with this disorder. Subsequently, the STSL locus has been further localized to a less than 2 centimorgans (cM) region.

In 2001, The STSL locus was found to be comprises two genes, ABCG5 and ABCG8, encoding 2 members of the ABC-transporter family, named sterolin-1 and sterolin-2, respectively. , Sterolin-2, discovered after sterolin-1, is located <400 base pair (bp) upstream of sterolin-1 in the opposite orientation.