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==Structure of the Grem2-GDF5 Inhibitory Complex==
==Structure of the Grem2-GDF5 Inhibitory Complex==
<StructureSection load='5hk5' size='340' side='right' caption='[[5hk5]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
<StructureSection load='5hk5' size='340' side='right'caption='[[5hk5]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5hk5]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HK5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HK5 FirstGlance]. <br>
<table><tr><td colspan='2'>[[5hk5]] is a 8 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=5HK5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HK5 FirstGlance]. <br>
</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=5hk5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hk5 OCA], [http://pdbe.org/5hk5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hk5 RCSB], [http://www.ebi.ac.uk/pdbsum/5hk5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5hk5 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]] 2.9&#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=5hk5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hk5 OCA], [https://pdbe.org/5hk5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hk5 RCSB], [https://www.ebi.ac.uk/pdbsum/5hk5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hk5 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/GDF5_HUMAN GDF5_HUMAN]] Defects in GDF5 are the cause of acromesomelic chondrodysplasia Grebe type (AMDG) [MIM:[http://omim.org/entry/200700 200700]]. Acromesomelic chondrodysplasias are rare hereditary skeletal disorders characterized by short stature, very short limbs, and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers). AMDG is an autosomal recessive form characterized by normal axial skeletons and missing or fused skeletal elements within the hands and feet.<ref>PMID:9288098</ref>  Defects in GDF5 are the cause of acromesomelic chondrodysplasia Hunter-Thompson type (AMDH) [MIM:[http://omim.org/entry/201250 201250]]. AMDH is an autosomal recessive form of dwarfism. Patients have limb abnormalities, with the middle and distal segments being most affected and the lower limbs more affected than the upper. AMDH is characterized by normal axial skeletons and missing or fused skeletal elements within the hands and feet.  Defects in GDF5 are the cause of brachydactyly type C (BDC) [MIM:[http://omim.org/entry/113100 113100]]. BDC is an autosomal dominant disorder characterized by an abnormal shortness of the fingers and toes. Note=Some BDC patients with GDF5 mutations also manifest clinical features of ASPED angel-shaped phalango-epiphyseal dysplasia (ASPED), an autosomal dominant skeletal abnormality characterized by a typical angel-shaped phalanx, brachydactyly, specific radiological findings, abnormal dentition, hip dysplasia, and delayed bone age. This suggests that BDC and ASPED are part of the same clinical spectrum (PubMed:22828468).<ref>PMID:22828468</ref> <ref>PMID:14735582</ref>  Defects in GDF5 are the cause of Du Pan syndrome (DPS) [MIM:[http://omim.org/entry/228900 228900]]; also known as fibular hypoplasia and complex brachydactyly. Du Pan syndrome is a rare autosomal recessive condition characterized by absence of the fibulae and severe acromesomelic limb shortening with small, non-functional toes. Although milder, the phenotype resembles the autosomal recessive Hunter-Thompson and Grebe types of acromesomelic chondrodysplasia.<ref>PMID:12121354</ref> <ref>PMID:16222676</ref> <ref>PMID:18629880</ref>  Defects in GDF5 are a cause of symphalangism proximal syndrome (SYM1) [MIM:[http://omim.org/entry/185800 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.<ref>PMID:16127465</ref> <ref>PMID:16892395</ref> <ref>PMID:18283415</ref>  Defects in GDF5 are the cause of multiple synostoses syndrome type 2 (SYNS2) [MIM:[http://omim.org/entry/610017 610017]]. Multiple synostoses syndrome is an autosomal dominant condition characterized by progressive joint fusions of the fingers, wrists, ankles and cervical spine, characteristic facies and progressive conductive deafness.[:]<ref>PMID:16532400</ref>  Defects in GDF5 are a cause of brachydactyly type A2 (BDA2) [MIM:[http://omim.org/entry/112600 112600]]. Brachydactylies (BDs) are a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. They have been classified on an anatomic and genetic basis into five groups, A to E, including three subgroups (A1 to A3) that usually manifest as autosomal dominant traits.<ref>PMID:16127465</ref> <ref>PMID:18203755</ref>  Genetic variations in GDF5 are associated with susceptibility to osteoarthritis type 5 (OS5) [MIM:[http://omim.org/entry/612400 612400]]. Osteoarthritis is a degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis. Clinical symptoms include pain and joint stiffness often leading to significant disability and joint replacement.  Defects in GDF5 may be a cause of brachydactyly type A1 (BDA1) [MIM:[http://omim.org/entry/112500 112500]]. Brachydactylies (BDs) are a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. They have been classified on an anatomic and genetic basis into five groups, A to E, including three subgroups (A1 to A3) that usually manifest as autosomal dominant traits.<ref>PMID:20683927</ref> 
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/GREM2_MOUSE GREM2_MOUSE]] Cytokine that inhibits the activity of BMP2 and BMP4 in a dose-dependent manner. Antagonized BMP4-induced suppression of progesterone production in granulosa cells.<ref>PMID:15039429</ref> [[http://www.uniprot.org/uniprot/GDF5_HUMAN GDF5_HUMAN]] Could be involved in bone and cartilage formation. Chondrogenic signaling is mediated by the high-affinity receptor BMPR1B.<ref>PMID:15530414</ref> <ref>PMID:19229295</ref> 
[https://www.uniprot.org/uniprot/GREM2_MOUSE GREM2_MOUSE] Cytokine that inhibits the activity of BMP2 and BMP4 in a dose-dependent manner. Antagonized BMP4-induced suppression of progesterone production in granulosa cells.<ref>PMID:15039429</ref>  
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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</div>
</div>
<div class="pdbe-citations 5hk5" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 5hk5" style="background-color:#fffaf0;"></div>
==See Also==
*[[Growth differentiation factor 3D STRUCTURES|Growth differentiation factor 3D STRUCTURES]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Nolan, K]]
[[Category: Homo sapiens]]
[[Category: Read, R J]]
[[Category: Large Structures]]
[[Category: Thompson, T B]]
[[Category: Mus musculus]]
[[Category: Bone morphogenetic protein]]
[[Category: Nolan K]]
[[Category: Cytokine]]
[[Category: Read RJ]]
[[Category: Dan-family]]
[[Category: Thompson TB]]

Latest revision as of 10:39, 9 August 2023

Structure of the Grem2-GDF5 Inhibitory ComplexStructure of the Grem2-GDF5 Inhibitory Complex

Structural highlights

5hk5 is a 8 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 2.9Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GREM2_MOUSE Cytokine that inhibits the activity of BMP2 and BMP4 in a dose-dependent manner. Antagonized BMP4-induced suppression of progesterone production in granulosa cells.[1]

Publication Abstract from PubMed

The DAN family, including Gremlin-1 and Gremlin-2 (Grem1 and Grem2), represents a large family of secreted BMP (bone morphogenetic protein) antagonists. However, how DAN proteins specifically inhibit BMP signaling has remained elusive. Here, we report the structure of Grem2 bound to GDF5 at 2.9-A resolution. The structure reveals two Grem2 dimers binding perpendicularly to each GDF5 monomer, resembling an H-like structure. Comparison to the unbound Grem2 structure reveals a dynamic N terminus that undergoes significant transition upon complex formation, leading to simultaneous interaction with the type I and type II receptor motifs on GDF5. Binding studies show that DAN-family members can interact with BMP-type I receptor complexes, whereas Noggin outcompetes the type I receptor for ligand binding. Interestingly, Grem2-GDF5 forms a stable aggregate-like structure in vitro that is not clearly observed for other antagonists, including Noggin and Follistatin. These findings exemplify the structural and functional diversity across the various BMP antagonist families.

Structure of Gremlin-2 in Complex with GDF5 Gives Insight into DAN-Family-Mediated BMP Antagonism.,Nolan K, Kattamuri C, Rankin SA, Read RJ, Zorn AM, Thompson TB Cell Rep. 2016 Aug 23;16(8):2077-86. doi: 10.1016/j.celrep.2016.07.046. Epub 2016, Aug 11. PMID:27524626[2]

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

See Also

References

  1. ↑ Sudo S, Avsian-Kretchmer O, Wang LS, Hsueh AJ. Protein related to DAN and cerberus is a bone morphogenetic protein antagonist that participates in ovarian paracrine regulation. J Biol Chem. 2004 May 28;279(22):23134-41. Epub 2004 Mar 23. PMID:15039429 doi:10.1074/jbc.M402376200
  2. ↑ Nolan K, Kattamuri C, Rankin SA, Read RJ, Zorn AM, Thompson TB. Structure of Gremlin-2 in Complex with GDF5 Gives Insight into DAN-Family-Mediated BMP Antagonism. Cell Rep. 2016 Aug 23;16(8):2077-86. doi: 10.1016/j.celrep.2016.07.046. Epub 2016, Aug 11. PMID:27524626 doi:http://dx.doi.org/10.1016/j.celrep.2016.07.046

5hk5, resolution 2.90Å

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