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N-linked glycosylation is an essential process in protein modification. This form of glycosylation is important in the folding and sorting of proteins in the endoplasmic reticulum (ER) and the interaction between proteins and cells. <ref name="Bai2018">DOI 10.1038/nature25755</ref> In humans, N-linked glycosylation is catalyzed co-translationally by an enzyme complex called oligosaccharyltransferase complex A (OST-A) in the rough ER. This means that the peptide chain is glycosylated by this complex as it is synthesized by the ribosome and enters the ER lumen through translocon protein Sec61.<ref name="Lu">DOI 10.1073/pnas.1806034115</ref> As suggested by the name, this enzyme complex transfers the high mannose fourteen-sugar chain from a lipid-linked oligosaccharide donor containing dolichol pyrophosphate to the peptide chain containing the Asn-X-Thr (N-X-T) sequence, where X is any amino acid but not Proline.<ref name="Bai2018"/> In addition, this enzyme complex is also part of the glycosyltransferase-C (GT-C) fold, which is a protein that has a transmembrane helical domain and a mix of α/β soluble domains.<ref name="Bai2019">DOI 10.1111/febs.14705</ref> On this page, the structure of the OST-A and its components; its mechanism, and diseases associated with this complex are discussed.
N-linked glycosylation is an essential process in protein modification. This form of glycosylation is important in the folding and sorting of proteins in the endoplasmic reticulum (ER) and the interaction between proteins and cells. <ref name="Bai2018">DOI 10.1038/nature25755</ref> In humans, N-linked glycosylation is catalyzed co-translationally by an enzyme complex called oligosaccharyltransferase complex A (OST-A) in the rough ER. This means that the peptide chain is glycosylated by this complex as it is synthesized by the ribosome and enters the ER lumen through translocon protein Sec61.<ref name="Lu">DOI 10.1073/pnas.1806034115</ref> As suggested by the name, this enzyme complex transfers the high mannose fourteen-sugar chain from a lipid-linked oligosaccharide donor containing dolichol pyrophosphate to the peptide chain containing the Asn-X-Thr (N-X-T) sequence, where X is any amino acid but not Proline.<ref name="Bai2018"/> In addition, this enzyme complex is also part of the glycosyltransferase-C (GT-C) fold, which is a protein that has a transmembrane helical domain and a mix of α/β soluble domains.<ref name="Bai2019">DOI 10.1111/febs.14705</ref> On this page, the structure of the OST-A and its components; its mechanism, and diseases associated with this complex are discussed.
== Structure ==
== Structure ==
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The human OST-A complex is a transmembrane protein that has 27 transmembrane helices integrated into the endoplasmic reticulum (ER) outer membrane with soluble domains on both the cytosolic side and the luminal side of the membrane (Ramirez et. al. 2019).<ref name="Ramirez">DOI 10.1126/science.aaz3505</ref> However, most of the functional sites of the complex are found on the luminal side. The OST-A complex consists of three sub-complexes with a total of nine subunits. All subunits have a transmembrane domain and soluble domains. The subcomplex I consists of two subunits: transmembrane protein 258 (TMEM258) and robophorin-1 (RPN-1). The subcomplex II consists of four subunits: STT3A, OST 4 kDa subunit (OST4), keratinocyte-associated protein 2 (KCP2), and DC2. Lastly, the subcomplex III consists of three subunits: defender against cell death 1 (DAD1), OST 48 kDa subunit (OST48), and ribophorin-2 (RPN-2) (Mohanty et. al. 2020).<ref name="Mohanty">DOI 10.3390/biom10040624</ref> The transmembrane domains of TMEM258 and RPN-1 are also in close proximity to a protein called malectin, which is believed to be involved in quality control in protein synthesis (Ramirez et. al. 2019).<ref name="Ramirez"/> In addition, the OST-A complex is associated with a translocon protein in the ER membrane called Sec61. The C-terminal of the RPN-1 subunit also forms a 4-helix bundle that specifically binds to the ribosome in the cytosol (Ramirez et. al. 2019).<ref name="Ramirez"/>
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The human OST-A complex is a transmembrane protein that has 27 transmembrane helices integrated into the endoplasmic reticulum (ER) outer membrane with soluble domains on both the cytosolic side and the luminal side of the membrane.<ref name="Ramirez">DOI 10.1126/science.aaz3505</ref> However, most of the functional sites of the complex are found on the luminal side. The OST-A complex consists of three sub-complexes with a total of nine subunits. All subunits have a transmembrane domain and soluble domains. The subcomplex I consists of two subunits: transmembrane protein 258 (TMEM258) and robophorin-1 (RPN-1). The subcomplex II consists of four subunits: STT3A, OST 4 kDa subunit (OST4), keratinocyte-associated protein 2 (KCP2), and DC2. Lastly, the subcomplex III consists of three subunits: defender against cell death 1 (DAD1), OST 48 kDa subunit (OST48), and ribophorin-2 (RPN-2).<ref name="Mohanty">DOI 10.3390/biom10040624</ref> The transmembrane domains of TMEM258 and RPN-1 are also in close proximity to a protein called malectin, which is believed to be involved in quality control in protein synthesis.<ref name="Ramirez"/> In addition, the OST-A complex is associated with a translocon protein in the ER membrane called Sec61. The C-terminal of the RPN-1 subunit also forms a 4-helix bundle that specifically binds to the ribosome in the cytosol.<ref name="Ramirez"/>
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The STT3A subunit consists of thirteen transmembrane helices and a mixture of alpha-helices and beta-sheet on their ER-luminal side. The N-terminal of this subunit is on the cytosolic side while the C-terminal is on the luminal side (Ramirez 2019).<ref name ="Ramirez"/> The catalytic of the OST-A complex is in this subunit, making it the most conserved and central subunit of the whole complex. It is homologous to the oligosaccharyltransferase in other species, such as PglB in some bacteria and AglB in archaea (Lara et. al. 2017).<ref name="Lara">DOI 10.1074/jbc.m117.779421</ref> The TMEM258 has two transmembrane helices with both N- and C-terminals on the luminal side. The RPN-1 and OST48 have a similar structure with one C-terminal transmembrane helix and N-terminal anti-parallel beta-sheet on the luminal side. The difference between the two subunits is that RPN-1 has a C-terminal helix bundle on the cytosolic side while OST48 has two helices on their luminal side. The OST4 subunit only consists of one transmembrane helix with N-terminal on the luminal side and the C-terminal on the cytosolic side. DC2 and DAD1 both have three transmembrane helices with the N-terminal from the cytosolic side and the C-terminal from the luminal side. However, DAD1 has a C-terminal helix on the cytosolic side. The RPN-2 subunit has three transmembrane helices and the anti-parallel beta-sheet at the N-terminal on the luminal side (Rameriz et. al. 2019).<ref name="Ramirez"/> Lastly, the KCP2 subunit has four transmembrane helices with both C- and N-terminals on the cytosolic side (Mohanty et. al. 2020).<ref name="Mohanty"/>
== Active Site ==
== Active Site ==

Revision as of 18:11, 21 April 2022

Human Oligosaccharyltransferase complex A (OST-A)

The structure of the oligosaccharyltransferase complex A (OST-A)

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References

  1. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
  2. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
  3. ↑ 3.0 3.1 Bai L, Wang T, Zhao G, Kovach A, Li H. The atomic structure of a eukaryotic oligosaccharyltransferase complex. Nature. 2018 Jan 22. pii: nature25755. doi: 10.1038/nature25755. PMID:29466327 doi:http://dx.doi.org/10.1038/nature25755
  4. ↑ Lu H, Fermaintt CS, Cherepanova NA, Gilmore R, Yan N, Lehrman MA. Mammalian STT3A/B oligosaccharyltransferases segregate N-glycosylation at the translocon from lipid-linked oligosaccharide hydrolysis. Proc Natl Acad Sci U S A. 2018 Sep 18;115(38):9557-9562. doi:, 10.1073/pnas.1806034115. Epub 2018 Sep 4. PMID:30181269 doi:http://dx.doi.org/10.1073/pnas.1806034115
  5. ↑ Bai L, Li H. Cryo-EM is uncovering the mechanism of eukaryotic protein N-glycosylation. FEBS J. 2019 May;286(9):1638-1644. doi: 10.1111/febs.14705. Epub 2018 Dec 3. PMID:30450807 doi:http://dx.doi.org/10.1111/febs.14705
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Ramirez AS, Kowal J, Locher KP. Cryo-electron microscopy structures of human oligosaccharyltransferase complexes OST-A and OST-B. Science. 2019 Dec 13;366(6471):1372-1375. doi: 10.1126/science.aaz3505. PMID:31831667 doi:http://dx.doi.org/10.1126/science.aaz3505
  7. ↑ 7.0 7.1 Mohanty S, Chaudhary BP, Zoetewey D. Structural Insight into the Mechanism of N-Linked Glycosylation by Oligosaccharyltransferase. Biomolecules. 2020 Apr 17;10(4). pii: biom10040624. doi: 10.3390/biom10040624. PMID:32316603 doi:http://dx.doi.org/10.3390/biom10040624
  8. ↑ Lara P, Ojemalm K, Reithinger J, Holgado A, Maojun Y, Hammed A, Mattle D, Kim H, Nilsson I. Refined topology model of the STT3/Stt3 protein subunit of the oligosaccharyltransferase complex. J Biol Chem. 2017 Jul 7;292(27):11349-11360. doi: 10.1074/jbc.M117.779421. Epub, 2017 May 16. PMID:28512128 doi:http://dx.doi.org/10.1074/jbc.M117.779421

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