7ag0: Difference between revisions

Revision as of 07:51, 7 February 2024

Complex between the bone morphogenetic protein 2 and its antagonist Noggin

Structural highlights

7ag0 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.104Å
Ligands:	GOL
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

NOGG_HUMAN Defects in NOG are a cause of symphalangism proximal syndrome (SYM1) [MIM:185800. SYM1 is characterized by the hereditary absence of the proximal interphalangeal (PIP) joints (Cushing symphalangism). Severity of PIP joint involvement diminishes towards the radial side. Distal interphalangeal joints are less frequently involved and metacarpophalangeal joints are rarely affected whereas carpal bone malformation and fusion are common. In the lower extremities, tarsal bone coalition is common. Conducive hearing loss is seen and is due to fusion of the stapes to the petrous part of the temporal bone.^[1] ^[2] ^[3] ^[4] Defects in NOG are the cause of multiple synostoses syndrome type 1 (SYNS1) [MIM:186500; also known as synostoses, multiple, with brachydactyly/symphalangism-brachydactyly syndrome. SYNS1 is characterized by tubular-shaped (hemicylindrical) nose with lack of alar flare, otosclerotic deafness, and multiple progressive joint fusions commencing in the hand. The joint fusions are progressive, commencing in the fifth proximal interphalangeal joint in early childhood (or at birth in some individuals) and progressing in an ulnar-to-radial and proximal-to-distal direction. With increasing age, ankylosis of other joints, including the cervical vertebrae, hips, and humeroradial joints, develop.^[5] Defects in NOG are the cause of tarsal-carpal coalition syndrome (TCC) [MIM:186570. TCC is an autosomal dominant disorder characterized by fusion of the carpals, tarsals and phalanges, short first metacarpals causing brachydactyly, and humeroradial fusion. TCC is allelic to SYM1, and different mutations in NOG can result in either TCC or SYM1 in different families.^[6] Defects in NOG are a cause of stapes ankylosis with broad thumb and toes (SABTS) [MIM:184460; also known as Teunissen-Cremers syndrome. SABTS is a congenital autosomal dominant disorder that includes hyperopia, a hemicylindrical nose, broad thumbs, great toes, and other minor skeletal anomalies but lacked carpal and tarsal fusion and symphalangism.^[7] Defects in NOG are the cause of brachydactyly type B2 (BDB2) [MIM:611377. BDB2 is a subtype of brachydactyly characterized by hypoplasia/aplasia of distal phalanges in combination with distal symphalangism, fusion of carpal/tarsal bones, and partial cutaneous syndactyly.^[8]

Function

NOGG_HUMAN Essential for cartilage morphogenesis and joint formation. Inhibitor of bone morphogenetic proteins (BMP) signaling which is required for growth and patterning of the neural tube and somite.^[9]

References

↑ Gong Y, Krakow D, Marcelino J, Wilkin D, Chitayat D, Babul-Hirji R, Hudgins L, Cremers CW, Cremers FP, Brunner HG, Reinker K, Rimoin DL, Cohn DH, Goodman FR, Reardon W, Patton M, Francomano CA, Warman ML. Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nat Genet. 1999 Mar;21(3):302-4. PMID:10080184 doi:10.1038/6821
↑ Takahashi T, Takahashi I, Komatsu M, Sawaishi Y, Higashi K, Nishimura G, Saito H, Takada G. Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome. Clin Genet. 2001 Dec;60(6):447-51. PMID:11846737
↑ Mangino M, Flex E, Digilio MC, Giannotti A, Dallapiccola B. Identification of a novel NOG gene mutation (P35S) in an Italian family with symphalangism. Hum Mutat. 2002 Mar;19(3):308. PMID:11857750 doi:10.1002/humu.9016
↑ van den Ende JJ, Mattelaer P, Declau F, Vanhoenacker F, Claes J, Van Hul E, Baten E. The facio-audio-symphalangism syndrome in a four generation family with a nonsense mutation in the NOG-gene. Clin Dysmorphol. 2005 Apr;14(2):73-80. PMID:15770128
↑ Rudnik-Schoneborn S, Takahashi T, Busse S, Schmidt T, Senderek J, Eggermann T, Zerres K. Facioaudiosymphalangism syndrome and growth acceleration associated with a heterozygous NOG mutation. Am J Med Genet A. 2010 Jun;152A(6):1540-4. doi: 10.1002/ajmg.a.33387. PMID:20503332 doi:10.1002/ajmg.a.33387
↑ Dixon ME, Armstrong P, Stevens DB, Bamshad M. Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism. Genet Med. 2001 Sep-Oct;3(5):349-53. PMID:11545688 doi:10.109700125817-200109000-00004
↑ Brown DJ, Kim TB, Petty EM, Downs CA, Martin DM, Strouse PJ, Moroi SE, Milunsky JM, Lesperance MM. Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin. Am J Hum Genet. 2002 Sep;71(3):618-24. Epub 2002 Jun 27. PMID:12089654 doi:10.1086/342067
↑ Lehmann K, Seemann P, Silan F, Goecke TO, Irgang S, Kjaer KW, Kjaergaard S, Mahoney MJ, Morlot S, Reissner C, Kerr B, Wilkie AO, Mundlos S. A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN. Am J Hum Genet. 2007 Aug;81(2):388-96. Epub 2007 Jun 8. PMID:17668388 doi:10.1086/519697
↑ Groppe J, Greenwald J, Wiater E, Rodriguez-Leon J, Economides AN, Kwiatkowski W, Affolter M, Vale WW, Belmonte JC, Choe S. Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature. 2002 Dec 12;420(6916):636-42. PMID:12478285 doi:10.1038/nature01245

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Gong Y, Krakow D, Marcelino J, Wilkin D, Chitayat D, Babul-Hirji R, Hudgins L, Cremers CW, Cremers FP, Brunner HG, Reinker K, Rimoin DL, Cohn DH, Goodman FR, Reardon W, Patton M, Francomano CA, Warman ML. Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nat Genet. 1999 Mar;21(3):302-4. PMID:10080184 doi:10.1038/6821

[2] Takahashi T, Takahashi I, Komatsu M, Sawaishi Y, Higashi K, Nishimura G, Saito H, Takada G. Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome. Clin Genet. 2001 Dec;60(6):447-51. PMID:11846737

[3] Mangino M, Flex E, Digilio MC, Giannotti A, Dallapiccola B. Identification of a novel NOG gene mutation (P35S) in an Italian family with symphalangism. Hum Mutat. 2002 Mar;19(3):308. PMID:11857750 doi:10.1002/humu.9016

[4] van den Ende JJ, Mattelaer P, Declau F, Vanhoenacker F, Claes J, Van Hul E, Baten E. The facio-audio-symphalangism syndrome in a four generation family with a nonsense mutation in the NOG-gene. Clin Dysmorphol. 2005 Apr;14(2):73-80. PMID:15770128

[5] Rudnik-Schoneborn S, Takahashi T, Busse S, Schmidt T, Senderek J, Eggermann T, Zerres K. Facioaudiosymphalangism syndrome and growth acceleration associated with a heterozygous NOG mutation. Am J Med Genet A. 2010 Jun;152A(6):1540-4. doi: 10.1002/ajmg.a.33387. PMID:20503332 doi:10.1002/ajmg.a.33387

[6] Dixon ME, Armstrong P, Stevens DB, Bamshad M. Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism. Genet Med. 2001 Sep-Oct;3(5):349-53. PMID:11545688 doi:10.109700125817-200109000-00004

[7] Brown DJ, Kim TB, Petty EM, Downs CA, Martin DM, Strouse PJ, Moroi SE, Milunsky JM, Lesperance MM. Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin. Am J Hum Genet. 2002 Sep;71(3):618-24. Epub 2002 Jun 27. PMID:12089654 doi:10.1086/342067

[8] Lehmann K, Seemann P, Silan F, Goecke TO, Irgang S, Kjaer KW, Kjaergaard S, Mahoney MJ, Morlot S, Reissner C, Kerr B, Wilkie AO, Mundlos S. A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN. Am J Hum Genet. 2007 Aug;81(2):388-96. Epub 2007 Jun 8. PMID:17668388 doi:10.1086/519697

[9] Groppe J, Greenwald J, Wiater E, Rodriguez-Leon J, Economides AN, Kwiatkowski W, Affolter M, Vale WW, Belmonte JC, Choe S. Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature. 2002 Dec 12;420(6916):636-42. PMID:12478285 doi:10.1038/nature01245

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@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[7ag0]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AG0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AG0 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></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]] 3.104&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></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=7ag0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ag0 OCA], [https://pdbe.org/7ag0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ag0 RCSB], [https://www.ebi.ac.uk/pdbsum/7ag0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ag0 ProSAT]</span></td></tr>
 </table>
@@ Line 11: / Line 12: @@
 == Function ==
 [https://www.uniprot.org/uniprot/NOGG_HUMAN NOGG_HUMAN] Essential for cartilage morphogenesis and joint formation. Inhibitor of bone morphogenetic proteins (BMP) signaling which is required for growth and patterning of the neural tube and somite.<ref>PMID:12478285</ref>
-<div style="background-color:#fffaf0;">
-== Publication Abstract from PubMed ==
-Bone morphogenetic proteins (BMPs) are secreted cytokines belonging to the transforming growth factor-beta superfamily. New therapeutic approaches based on BMP activity, particularly for cartilage and bone repair, have sparked considerable interest; however, a lack of understanding of their interaction pathways and the side effects associated with their use as biopharmaceuticals have dampened initial enthusiasm. Here, we used BMP-2 as a model system to gain further insight into both the relationship between structure and function in BMPs and the principles that govern affinity for their cognate antagonist Noggin. We produced BMP-2 and Noggin as inclusion bodies in Escherichia coli and developed simple and efficient protocols for preparing pure and homogeneous (in terms of size distribution) solutions of the native dimeric forms of the two proteins. The identity and integrity of the proteins were confirmed using mass spectrometry. Additionally, several in vitro cell-based assays, including enzymatic measurements, RT-qPCR, and matrix staining, demonstrated their biological activity during cell chondrogenic and hypertrophic differentiation. Furthermore, we characterized the simple 1:1 noncovalent interaction between the two ligands (K(D)ca. 0.4 nM) using bio-layer interferometry and solved the crystal structure of the complex using X-ray diffraction methods. We identified the residues and binding forces involved in the interaction between the two proteins. Finally, results obtained with the BMP-2 N102D mutant suggest that Noggin is remarkably flexible and able to accommodate major structural changes at the BMP-2 level. Altogether, our findings provide insights into BMP-2 activity and reveal the molecular details of its interaction with Noggin.
-Structural analysis of the interaction between human cytokine BMP-2 and the antagonist Noggin reveals molecular details of cell chondrogenesis inhibition.,Robert C, Kerff F, Bouillenne F, Gavage M, Vandevenne M, Filee P, Matagne A J Biol Chem. 2023 Feb;299(2):102892. doi: 10.1016/j.jbc.2023.102892. Epub 2023 , Jan 13. PMID:36642181<ref>PMID:36642181</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 7ag0" style="background-color:#fffaf0;"></div>
 ==See Also==

7ag0: Difference between revisions

Revision as of 07:51, 7 February 2024

Complex between the bone morphogenetic protein 2 and its antagonist Noggin

Structural highlights

Disease

Function

See Also

References

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