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6gff

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Structure of GARP (LRRC32) in complex with latent TGF-beta1 and MHG-8 Fab

Structural highlights

6gff is a 14 chain structure with sequence from Human and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	TGFB1, TGFB (HUMAN), LRRC32, D11S833E, GARP (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[TGFB1_HUMAN] Defects in TGFB1 are the cause of Camurati-Engelmann disease (CE) [MIM:131300]; also known as progressive diaphyseal dysplasia 1 (DPD1). CE is an autosomal dominant disorder characterized by hyperostosis and sclerosis of the diaphyses of long bones. The disease typically presents in early childhood with pain, muscular weakness and waddling gait, and in some cases other features such as exophthalmos, facial paralysis, hearing difficulties and loss of vision.^[1] ^[2] ^[3] ^[4] ^[5]

Function

[TGFB1_HUMAN] Multifunctional protein that controls proliferation, differentiation and other functions in many cell types. Many cells synthesize TGFB1 and have specific receptors for it. It positively and negatively regulates many other growth factors. It plays an important role in bone remodeling as it is a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts. [LRC32_HUMAN] Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space (PubMed:19750484, PubMed:19651619, PubMed:22278742). Associates specifically via disulfide bonds with the Latency-associated peptide (LAP), which is the regulatory chain of TGF-beta, and regulates integrin-dependent activation of TGF-beta (PubMed:22278742). Able to outcompete LTBP1 for binding to LAP regulatory chain of TGF-beta (PubMed:22278742). Controls activation of TGF-beta-1 (TGFB1) on the surface of activated regulatory T-cells (Tregs) (PubMed:19750484, PubMed:19651619). Required for epithelial fusion during palate development by regulating activation of TGF-beta-3 (TGFB3) (By similarity).[UniProtKB:G3XA59]^[6] ^[7] ^[8]

Publication Abstract from PubMed

Transforming growth factor-beta1 (TGF-beta1) is one of very few cytokines produced in a latent form, requiring activation to exert any of its vastly diverse effects on development, immunity, and cancer. Regulatory T cells (Tregs) suppress immune cells within close proximity by activating latent TGF-beta1 presented by GARP to integrin alphaVbeta8 on their surface. We solved the crystal structure of GARP:latent TGF-beta1 bound to an antibody that stabilizes the complex and blocks release of active TGF-beta1. This reveals how GARP exploits an unusual medley of interactions, including fold complementation by the N terminus of TGF-beta1, to chaperone and orient the cytokine for binding and activation by alphaVbeta8. Thus, this work further elucidates the mechanism of antibody-mediated blockade of TGF-beta1 activation and immunosuppression by Tregs.

Structural basis of latent TGF-beta1 presentation and activation by GARP on human regulatory T cells.,Lienart S, Merceron R, Vanderaa C, Lambert F, Colau D, Stockis J, van der Woning B, De Haard H, Saunders M, Coulie PG, Savvides SN, Lucas S Science. 2018 Oct 25. pii: science.aau2909. doi: 10.1126/science.aau2909. PMID:30361387^[9]

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

References

↑ Kinoshita A, Saito T, Tomita H, Makita Y, Yoshida K, Ghadami M, Yamada K, Kondo S, Ikegawa S, Nishimura G, Fukushima Y, Nakagomi T, Saito H, Sugimoto T, Kamegaya M, Hisa K, Murray JC, Taniguchi N, Niikawa N, Yoshiura K. Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nat Genet. 2000 Sep;26(1):19-20. PMID:10973241 doi:10.1038/79128
↑ Janssens K, Gershoni-Baruch R, Guanabens N, Migone N, Ralston S, Bonduelle M, Lissens W, Van Maldergem L, Vanhoenacker F, Verbruggen L, Van Hul W. Mutations in the gene encoding the latency-associated peptide of TGF-beta 1 cause Camurati-Engelmann disease. Nat Genet. 2000 Nov;26(3):273-5. PMID:11062463 doi:10.1038/81563
↑ Janssens K, ten Dijke P, Ralston SH, Bergmann C, Van Hul W. Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein. J Biol Chem. 2003 Feb 28;278(9):7718-24. Epub 2002 Dec 18. PMID:12493741 doi:10.1074/jbc.M208857200
↑ McGowan NW, MacPherson H, Janssens K, Van Hul W, Frith JC, Fraser WD, Ralston SH, Helfrich MH. A mutation affecting the latency-associated peptide of TGFbeta1 in Camurati-Engelmann disease enhances osteoclast formation in vitro. J Clin Endocrinol Metab. 2003 Jul;88(7):3321-6. PMID:12843182
↑ Kinoshita A, Fukumaki Y, Shirahama S, Miyahara A, Nishimura G, Haga N, Namba A, Ueda H, Hayashi H, Ikegawa S, Seidel J, Niikawa N, Yoshiura K. TGFB1 mutations in four new families with Camurati-Engelmann disease: confirmation of independently arising LAP-domain-specific mutations. Am J Med Genet A. 2004 May 15;127A(1):104-7. PMID:15103729 doi:10.1002/ajmg.a.20671
↑ Tran DQ, Andersson J, Wang R, Ramsey H, Unutmaz D, Shevach EM. GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells. Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13445-50. doi:, 10.1073/pnas.0901944106. Epub 2009 Jul 27. PMID:19651619 doi:http://dx.doi.org/10.1073/pnas.0901944106
↑ Stockis J, Colau D, Coulie PG, Lucas S. Membrane protein GARP is a receptor for latent TGF-beta on the surface of activated human Treg. Eur J Immunol. 2009 Dec;39(12):3315-22. doi: 10.1002/eji.200939684. PMID:19750484 doi:http://dx.doi.org/10.1002/eji.200939684
↑ Wang R, Zhu J, Dong X, Shi M, Lu C, Springer TA. GARP regulates the bioavailability and activation of TGFbeta. Mol Biol Cell. 2012 Mar;23(6):1129-39. doi: 10.1091/mbc.E11-12-1018. Epub 2012, Jan 25. PMID:22278742 doi:http://dx.doi.org/10.1091/mbc.E11-12-1018
↑ Lienart S, Merceron R, Vanderaa C, Lambert F, Colau D, Stockis J, van der Woning B, De Haard H, Saunders M, Coulie PG, Savvides SN, Lucas S. Structural basis of latent TGF-beta1 presentation and activation by GARP on human regulatory T cells. Science. 2018 Oct 25. pii: science.aau2909. doi: 10.1126/science.aau2909. PMID:30361387 doi:http://dx.doi.org/10.1126/science.aau2909

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6gff"

@@ Line 3: / Line 3: @@
 <StructureSection load='6gff' size='340' side='right' caption='[[6gff]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6gff]] is a 14 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GFF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GFF FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6gff]] is a 14 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GFF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GFF FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TGFB1, TGFB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), LRRC32, D11S833E, GARP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6gff FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gff OCA], [http://pdbe.org/6gff PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gff RCSB], [http://www.ebi.ac.uk/pdbsum/6gff PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gff ProSAT]</span></td></tr>
 </table>
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Mus musculus]]
 [[Category: Colau, D]]

6gff

From Proteopedia

Current revision

Structure of GARP (LRRC32) in complex with latent TGF-beta1 and MHG-8 Fab

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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