5t6p

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of therapeutic mAB AR20.5 in complex with MUC1 peptide

Structural highlights

5t6p is a 6 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.97Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MUC1_HUMAN Note=MUC1/CA 15-3 is used as a serological clinical marker of breast cancer to monitor response to breast cancer treatment and disease recurrence (PubMed:20816948). Decreased levels over time may be indicative of a positive response to treatment. Conversely, increased levels may indicate disease progression. At an early stage disease, only 21% of patients exhibit high MUC1/CA 15-3 levels, that is why CA 15-3 is not a useful screening test. Most antibodies target the highly immunodominant core peptide domain of 20 amino acid (APDTRPAPGSTAPPAHGVTS) tandem repeats. Some antibodies recognize glycosylated epitopes.

Function

MUC1_HUMAN The alpha subunit has cell adhesive properties. Can act both as an adhesion and an anti-adhesion protein. May provide a protective layer on epithelial cells against bacterial and enzyme attack.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] The beta subunit contains a C-terminal domain which is involved in cell signaling, through phosphorylations and protein-protein interactions. Modulates signaling in ERK, SRC and NF-kappa-B pathways. In activated T-cells, influences directly or indirectly the Ras/MAPK pathway. Promotes tumor progression. Regulates TP53-mediated transcription and determines cell fate in the genotoxic stress response. Binds, together with KLF4, the PE21 promoter element of TP53 and represses TP53 activity.^[10] ^[11] ^[12] ^[13] ^[14] ^[15] ^[16] ^[17] ^[18]

Publication Abstract from PubMed

In cancer cells, the glycoprotein Mucin 1 (MUC1) undergoes abnormal, truncated glycosylation. The truncated glycosylation exposes cryptic peptide epitopes that can be recognized by antibodies. Since these immunogenic regions are cancer specific, they represent ideal targets for therapeutic antibodies. We investigated the role of tumor-specific glycosylation on antigen recognition by the therapeutic antibody AR20.5. We explored the affinity of AR20.5 to a synthetic cancer-specific MUC1 glycopeptide and peptide. The antibody bound to the glycopeptide with an order of magnitude stronger affinity than the naked peptide. Given these results, we postulated that AR20.5 must specifically bind the carbohydrate as well as the peptide. Using X-ray crystallography, we examined this hypothesis by determining the structure of AR20.5 in complex with both peptide and glycopeptide. Surprisingly, the structure revealed that the carbohydrate did not form any specific polar contacts with the antibody. The high affinity of AR20.5 for the glycopeptide and the lack of specific binding contacts support a hypothesis that glycosylation of MUC1 stabilizes an extended bioactive conformation of the peptide recognized by the antibody. Since high affinity binding of AR20.5 to the MUC1 glycopeptide may not driven by specific antibody-antigen contacts, but rather evidence suggests that glycosylation alters the conformational equilibrium of the antigen, which allows the antibody to select the correct conformation. This study suggests a novel mechanism of antibody-antigen interaction and also suggests that glycosylation of MUC1 is important for the generation of high affinity therapeutic antibodies.

Glycosylation of MUC1 influences the binding of a therapeutic antibody by altering the conformational equilibrium of the antigen.,Movahedin M, Brooks TM, Supekar NT, Gokanapudi N, Boons GJ, Brooks CL Glycobiology. 2016 Dec 26. pii: cww131. doi: 10.1093/glycob/cww131. PMID:28025250^[19]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Yamamoto M, Bharti A, Li Y, Kufe D. Interaction of the DF3/MUC1 breast carcinoma-associated antigen and beta-catenin in cell adhesion. J Biol Chem. 1997 May 9;272(19):12492-4. PMID:9139698
↑ Ren J, Li Y, Kufe D. Protein kinase C delta regulates function of the DF3/MUC1 carcinoma antigen in beta-catenin signaling. J Biol Chem. 2002 May 17;277(20):17616-22. Epub 2002 Mar 4. PMID:11877440 doi:10.1074/jbc.M200436200
↑ Huang L, Ren J, Chen D, Li Y, Kharbanda S, Kufe D. MUC1 cytoplasmic domain coactivates Wnt target gene transcription and confers transformation. Cancer Biol Ther. 2003 Nov-Dec;2(6):702-6. PMID:14688481
↑ Wei X, Xu H, Kufe D. Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Cancer Cell. 2005 Feb;7(2):167-78. PMID:15710329 doi:10.1016/j.ccr.2005.01.008
↑ Huang L, Chen D, Liu D, Yin L, Kharbanda S, Kufe D. MUC1 oncoprotein blocks glycogen synthase kinase 3beta-mediated phosphorylation and degradation of beta-catenin. Cancer Res. 2005 Nov 15;65(22):10413-22. PMID:16288032 doi:65/22/10413
↑ Mukherjee P, Tinder TL, Basu GD, Gendler SJ. MUC1 (CD227) interacts with lck tyrosine kinase in Jurkat lymphoma cells and normal T cells. J Leukoc Biol. 2005 Jan;77(1):90-9. Epub 2004 Oct 28. PMID:15513966 doi:jlb.0604333
↑ Lillehoj EP, Lu W, Kiser T, Goldblum SE, Kim KC. MUC1 inhibits cell proliferation by a beta-catenin-dependent mechanism. Biochim Biophys Acta. 2007 Jul;1773(7):1028-38. Epub 2007 Apr 22. PMID:17524503 doi:S0167-4889(07)00092-4
↑ Wei X, Xu H, Kufe D. Human mucin 1 oncoprotein represses transcription of the p53 tumor suppressor gene. Cancer Res. 2007 Feb 15;67(4):1853-8. PMID:17308127 doi:67/4/1853
↑ Pochampalli MR, el Bejjani RM, Schroeder JA. MUC1 is a novel regulator of ErbB1 receptor trafficking. Oncogene. 2007 Mar 15;26(12):1693-701. Epub 2006 Sep 18. PMID:16983337 doi:1209976
↑ Yamamoto M, Bharti A, Li Y, Kufe D. Interaction of the DF3/MUC1 breast carcinoma-associated antigen and beta-catenin in cell adhesion. J Biol Chem. 1997 May 9;272(19):12492-4. PMID:9139698
↑ Ren J, Li Y, Kufe D. Protein kinase C delta regulates function of the DF3/MUC1 carcinoma antigen in beta-catenin signaling. J Biol Chem. 2002 May 17;277(20):17616-22. Epub 2002 Mar 4. PMID:11877440 doi:10.1074/jbc.M200436200
↑ Huang L, Ren J, Chen D, Li Y, Kharbanda S, Kufe D. MUC1 cytoplasmic domain coactivates Wnt target gene transcription and confers transformation. Cancer Biol Ther. 2003 Nov-Dec;2(6):702-6. PMID:14688481
↑ Wei X, Xu H, Kufe D. Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Cancer Cell. 2005 Feb;7(2):167-78. PMID:15710329 doi:10.1016/j.ccr.2005.01.008
↑ Huang L, Chen D, Liu D, Yin L, Kharbanda S, Kufe D. MUC1 oncoprotein blocks glycogen synthase kinase 3beta-mediated phosphorylation and degradation of beta-catenin. Cancer Res. 2005 Nov 15;65(22):10413-22. PMID:16288032 doi:65/22/10413
↑ Mukherjee P, Tinder TL, Basu GD, Gendler SJ. MUC1 (CD227) interacts with lck tyrosine kinase in Jurkat lymphoma cells and normal T cells. J Leukoc Biol. 2005 Jan;77(1):90-9. Epub 2004 Oct 28. PMID:15513966 doi:jlb.0604333
↑ Lillehoj EP, Lu W, Kiser T, Goldblum SE, Kim KC. MUC1 inhibits cell proliferation by a beta-catenin-dependent mechanism. Biochim Biophys Acta. 2007 Jul;1773(7):1028-38. Epub 2007 Apr 22. PMID:17524503 doi:S0167-4889(07)00092-4
↑ Wei X, Xu H, Kufe D. Human mucin 1 oncoprotein represses transcription of the p53 tumor suppressor gene. Cancer Res. 2007 Feb 15;67(4):1853-8. PMID:17308127 doi:67/4/1853
↑ Pochampalli MR, el Bejjani RM, Schroeder JA. MUC1 is a novel regulator of ErbB1 receptor trafficking. Oncogene. 2007 Mar 15;26(12):1693-701. Epub 2006 Sep 18. PMID:16983337 doi:1209976
↑ Movahedin M, Brooks TM, Supekar NT, Gokanapudi N, Boons GJ, Brooks CL. Glycosylation of MUC1 influences the binding of a therapeutic antibody by altering the conformational equilibrium of the antigen. Glycobiology. 2016 Dec 26. pii: cww131. doi: 10.1093/glycob/cww131. PMID:28025250 doi:http://dx.doi.org/10.1093/glycob/cww131

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5t6p"

Categories: Homo sapiens | Large Structures | Mus musculus | Brooks CL | Movahedin M

@@ Line 3: / Line 3: @@
 <StructureSection load='5t6p' size='340' side='right'caption='[[5t6p]], [[Resolution|resolution]] 1.97&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5t6p]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T6P OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5T6P FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5t6p]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T6P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5T6P FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5t6p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t6p OCA], [http://pdbe.org/5t6p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t6p RCSB], [http://www.ebi.ac.uk/pdbsum/5t6p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t6p ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.97&#8491;</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5t6p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t6p OCA], [https://pdbe.org/5t6p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5t6p RCSB], [https://www.ebi.ac.uk/pdbsum/5t6p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5t6p ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[https://www.uniprot.org/uniprot/MUC1_HUMAN MUC1_HUMAN] Note=MUC1/CA 15-3 is used as a serological clinical marker of breast cancer to monitor response to breast cancer treatment and disease recurrence (PubMed:20816948). Decreased levels over time may be indicative of a positive response to treatment. Conversely, increased levels may indicate disease progression. At an early stage disease, only 21% of patients exhibit high MUC1/CA 15-3 levels, that is why CA 15-3 is not a useful screening test. Most antibodies target the highly immunodominant core peptide domain of 20 amino acid (APDTRPAPGSTAPPAHGVTS) tandem repeats. Some antibodies recognize glycosylated epitopes.
+== Function ==
+[https://www.uniprot.org/uniprot/MUC1_HUMAN MUC1_HUMAN] The alpha subunit has cell adhesive properties. Can act both as an adhesion and an anti-adhesion protein. May provide a protective layer on epithelial cells against bacterial and enzyme attack.<ref>PMID:9139698</ref> <ref>PMID:11877440</ref> <ref>PMID:14688481</ref> <ref>PMID:15710329</ref> <ref>PMID:16288032</ref> <ref>PMID:15513966</ref> <ref>PMID:17524503</ref> <ref>PMID:17308127</ref> <ref>PMID:16983337</ref>   The beta subunit contains a C-terminal domain which is involved in cell signaling, through phosphorylations and protein-protein interactions. Modulates signaling in ERK, SRC and NF-kappa-B pathways. In activated T-cells, influences directly or indirectly the Ras/MAPK pathway. Promotes tumor progression. Regulates TP53-mediated transcription and determines cell fate in the genotoxic stress response. Binds, together with KLF4, the PE21 promoter element of TP53 and represses TP53 activity.<ref>PMID:9139698</ref> <ref>PMID:11877440</ref> <ref>PMID:14688481</ref> <ref>PMID:15710329</ref> <ref>PMID:16288032</ref> <ref>PMID:15513966</ref> <ref>PMID:17524503</ref> <ref>PMID:17308127</ref> <ref>PMID:16983337</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 15: / Line 20: @@
 </div>
 <div class="pdbe-citations 5t6p" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Brooks, C L]]
+[[Category: Mus musculus]]
-[[Category: Movahedin, M]]
+[[Category: Brooks CL]]
-[[Category: Antibody]]
+[[Category: Movahedin M]]
-[[Category: Fab]]
-[[Category: Immune system]]

5t6p

From Proteopedia

Current revision

Crystal structure of therapeutic mAB AR20.5 in complex with MUC1 peptide

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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