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This Sandbox is Reserved from Jan 13 through September 1, 2020 for use in the course CH462 Biochemistry II taught by R. Jeremy Johnson at the Butler University, Indianapolis, USA. This reservation includes Sandbox Reserved 1598 through Sandbox Reserved 1627.

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ABCG2 Multidrug Transporter

1 Background
2 Structural highlights
- 2.1 ATP Bound and Unbound Conformations
- 2.2 Cavities and Leucine Plug
3 Disease
- 3.1 Cancer

Background

The ABCG2 multidrug transporter is a membrane protein from the ATP-binding cassette (ABC) transporter family, specifically the G-subfamily. Also know as the breast cancer resistance protein (BCRP), ABCG2 has physiological roles in various tissue cells including the mammary gland and the blood-brain, blood-testis, and maternal-fetal barriers.^[1] ABCG2 protects cells by exporting xenobiotic molecules out of the cell using ATP hydrolysis. ABCG2 also affects the pharmacokinetics of many drugs and contributes to multidrug resistance.^[2]

Structural highlights

ABCG2 is a homodimer with each subunit containing two domains, the nucleotide binding domain and the transmembrane domain , which are fused together as a single peptide chain.^[1] The NBD is located inside of the cell and exposed to the cytosol while the TMD is embedded in the cell membrane and exposed to both the extracellular space and cytosol.

Figure 1. Domains of ABCG2 Multidrug transporter. The above protein is in the inward-facing conformation

ATP Bound and Unbound Conformations

As an ABC Transporter, ABCG2 exhibits ATPase activity in which the protein binds and hydrolyzes ATP. After the binding of a substrate, one molecule of causing a conformational change of the overall structure from an with no ATP bound to an . One molecule of ATP is hydrolyzed to transport substrates across the cell membrane while the second molecule of ATP is hydrolyzed to reset the transporter to its inward-facing conformation.^[3]

When ATP binds, α-helices in each NBD approximately 35° relative to their . This shift in the NBD causes slight shifts of α-helices in each TMD; these helices are relative to their . The overall shift from inward-facing to outward-facing promotes the transport of substrates through the transporter.^[2]

Cavities and Leucine Plug

Figure 2. Locations of Cavities 1 and 2 and the Leucine Plug in ABCG2. The above protein is in the inward-facing conformation

Substrates are transported through ABCG2 via two cavities separated by a leucine plug. acts as the multidrug binding pocket and is formed by helices at the interface of the subunits in the TMD. When ATP is not bound to the NBDs, Cavity 1 is in order to recruit substrates for transport. Cavity 1 is and full of nonpolar, hydrophobic residues and, as a result, prefers nonpolar, hydrophobic substrates, particularly flat, polycyclic molecules.^[1] Substrates, such as estrone sulfate, with residues from each subunit in Cavity 1.

After substrates bind in Cavity 1, ATP binds each NBD leading to the shift from inward-facing to outward-facing. The outward-facing conformation results in the in the TMD. This collapse closes Cavity 1 to the cytosol and forces the substrate to move forward to Cavity 2 as there is no longer room in Cavity 1 to accommodate substrates.^[2] , which is occluded when in the inward-facing conformation, is now open to the extracellular space and able to release the substrate. Cavity 2 contains a less hydrophobic environment and, as a result, substrates are released due to hydrophobic mismatch.^[1] in the external loop near the exit of Cavity 2 also help promote substrate release.^[2] Once Cavity 2 is empty, the protein can be converted to the inward-facing conformation via hydrolysis of ATP.

Cavities 1 and 2 are separated by a which likely acts as a substrate check-point during transport; removal of this plug has exhibited an increase in transport and a decrease in substrate specificity.^[2] After the substrate binds Cavity 1 and ATP molecules bind the NBDs, the to allow the substrate to enter Cavity 2. Once the substrate enters Cavity 2, the plug is able to reform and promotes substrate release and conversion to the inward-facing conformation.

Disease

Dysfunctions in ABCG2 is linked to hyperuricemia which can lead to gout, kidney disease, and hypertension, all of which are thought to be the result of impaired transport of uric acid. Additionally, the expression of ABCG2 correlates to poor prognosis and treatment outcome of certain cancers such as breast, ovarian, and lung.^[4]

Cancer

ABCG2 hinders cancer treatment by contributing to multidrug resistance in tumor cells. ABCG2 exports xenbiotics, including vital anti-cancer drugs, which results in the inability to treat cancer cells. The inhibition of ABCG2 would stop the transport of anti-cancer drugs out of cancer cells. Due to the potential the inhibition of ABCG2 to aid in cancer treatment, efforts have gone towards the development of specific inhibitors of ABCG2 and other ABC transporters. Inhibitors were derived from fungal toxin fumitremorgin C; however, many of those developed have neurotoxic effects.^[4]

References

^[1] ^[2] ^[3] ^[4]

↑ ^1.0 ^1.1 ^1.2 ^1.3 ^1.4 Taylor NMI, Manolaridis I, Jackson SM, Kowal J, Stahlberg H, Locher KP. Structure of the human multidrug transporter ABCG2. Nature. 2017 Jun 22;546(7659):504-509. doi: 10.1038/nature22345. Epub 2017 May, 29. PMID:28554189 doi:http://dx.doi.org/10.1038/nature22345
↑ ^2.0 ^2.1 ^2.2 ^2.3 ^2.4 ^2.5 Manolaridis I, Jackson SM, Taylor NMI, Kowal J, Stahlberg H, Locher KP. Cryo-EM structures of a human ABCG2 mutant trapped in ATP-bound and substrate-bound states. Nature. 2018 Nov;563(7731):426-430. doi: 10.1038/s41586-018-0680-3. Epub 2018 Nov, 7. PMID:30405239 doi:http://dx.doi.org/10.1038/s41586-018-0680-3
↑ ^3.0 ^3.1 Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MM. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat Rev Cancer. 2018 Jul;18(7):452-464. doi: 10.1038/s41568-018-0005-8. PMID:29643473 doi:http://dx.doi.org/10.1038/s41568-018-0005-8
↑ ^4.0 ^4.1 ^4.2 Jackson SM, Manolaridis I, Kowal J, Zechner M, Taylor NMI, Bause M, Bauer S, Bartholomaeus R, Bernhardt G, Koenig B, Buschauer A, Stahlberg H, Altmann KH, Locher KP. Structural basis of small-molecule inhibition of human multidrug transporter ABCG2. Nat Struct Mol Biol. 2018 Apr;25(4):333-340. doi: 10.1038/s41594-018-0049-1. Epub, 2018 Apr 2. PMID:29610494 doi:http://dx.doi.org/10.1038/s41594-018-0049-1

Student Contributors

Julia Pomeroy

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@@ Line 9: / Line 9: @@
 == Structural highlights ==
-ABCG2 is a homodimer with each subunit containing two domains, the nucleotide binding domain (NBD) and the transmembrane domain (TMD), which are fused together as a single peptide chain.<ref name="Taylor"/> The NBD is located inside of the cell and exposed to the cytosol while the TMD is embedded in the cell membrane and exposed to both the extracellular space and cytosol. [[Image:membrane domains.png|200 px|right|thumb|Figure 1. Domains of ABCG2 Multidrug transporter. The above protein is in the inward-facing conformation]]
+ABCG2 is a homodimer with each subunit containing two domains, the nucleotide binding domain <scene name='83/832932/Overall_structure_nbd_unbound/1'>(NBD)</scene> and the transmembrane domain <scene name='83/832932/Overall_structure_tmd_unbound/2'>(TMD)</scene>, which are fused together as a single peptide chain.<ref name="Taylor"/> The NBD is located inside of the cell and exposed to the cytosol while the TMD is embedded in the cell membrane and exposed to both the extracellular space and cytosol. [[Image:membrane domains.png|200 px|right|thumb|Figure 1. Domains of ABCG2 Multidrug transporter. The above protein is in the inward-facing conformation]]
 ===ATP Bound and Unbound Conformations===
-As an [https://en.wikipedia.org/wiki/ATP-binding_cassette_transporter ABC Transporter], ABCG2 exhibits ATPase activity in which the protein binds and hydrolyzes ATP. After the binding of a substrate, one molecule of <scene name='83/832932/Atp_bound_use2/1'>ATP binds each NBD</scene> causing a conformational change of the overall structure from an <scene name='83/832932/Overall_use_2/1'>inward-facing conformation</scene> with no ATP bound to a <scene name='83/832932/Atp_bound_use/1'>outward-facing conformation</scene>. One molecule of ATP is hydrolyzed to transport substrates across the cell membrane while the second molecule of ATP is hydrolyzed to reset the transporter to its inward-facing conformation.<ref name="Robey"/>
+As an [https://en.wikipedia.org/wiki/ATP-binding_cassette_transporter ABC Transporter], ABCG2 exhibits ATPase activity in which the protein binds and hydrolyzes ATP. After the binding of a substrate, one molecule of <scene name='83/832932/Atp_bound_use2/1'>ATP binds each NBD</scene> causing a conformational change of the overall structure from an <scene name='83/832932/Overall_use_2/1'>inward-facing conformation</scene> with no ATP bound to an <scene name='83/832932/Outward_facing_conformation/1'>outward-facing conformation</scene>. One molecule of ATP is hydrolyzed to transport substrates across the cell membrane while the second molecule of ATP is hydrolyzed to reset the transporter to its inward-facing conformation.<ref name="Robey"/>
 When ATP binds, α-helices in each NBD <scene name='83/832932/Atp_bound_nbd/1'>rotate</scene> approximately 35° relative to their <scene name='83/832932/Overall_structure_nbd_unbound/1'>inward-facing conformations</scene>. This shift in the NBD causes slight shifts of α-helices in each TMD; these helices are <scene name='83/832932/Atp_bound_use_tmd/1'>pushed toward each other</scene> relative to their <scene name='83/832932/Overall_structure_tmd_unbound/2'>inward-facing conformations</scene>. The overall shift from inward-facing to outward-facing promotes the transport of substrates through the transporter.<ref name="Manolaridis"/>

Sandbox Reserved 1606

From Proteopedia

Revision as of 20:23, 6 April 2020

ABCG2 Multidrug Transporter

Contents

Background

Structural highlights

ATP Bound and Unbound Conformations

Cavities and Leucine Plug

Disease

Cancer

References

Student Contributors

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