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From Proteopedia
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Contents |
YourMacromolecule
Introduction
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Bone Morphogenetic Protein 7 (BMP-7) is a protein that is involved in a variety of aspects of embryonic and adult development. Some of the areas it is involved in are neural tissue induction, the formation of bones and joints in the skeletal system, and neurogenesis in the adult brain. Neural induction is the process by which the undifferentiated ectoderm layer of the embryo are signaled to form neuro-ectoderm cells by the mesoderm. These differentiated cells will become neural cells. Only some of the cells are signaled to differentiate in this way, and the rest become the epidermis. In bone formation, first a flexible membrane is formed in the embryo that develops into cartilage. As the embryo develops, signaling through proteins in the BMP family including BMP-7 causing ossification to occur, which is the process of forming bone, replacing the cartilage membranes. This can be seen in the development of the skull. BMP can also signal for cartilage to transform to bone, which is how much of the rest of the skeleton develops. One of the most important aspects of BMP-7 is its role in neurogenesis in the adult brain. Neurogenesis is the process by which new neurons are created in the adult brain. Initially it was thought that proteins in the BMP family would inhibit neurogenesis unless deactivated by the antagonist, Noggin. But when the levels of neurogenesis were examined with the over expression and signalling of BMP, there was no inhibition of the creation of neurons. In fact further research has shown that BMP-mediated signalling is required to allow neurogenesis in adults.
Because BMP’s are crucial in much of the development and upkeep of many organs and systems, there are many disease that can arise or be affected by dysfunctional BMP genes and proteins. The incorrect implementation of BMP-7 during development can result in issues with skeletal and neural development. BMP-7 can also have impacts after the initial fetal development. Research has linked a lack of BMP-7 signalling to the progression of gastrointestinal cancers, particularly colon and esophageal cancer.
There have also been developments in using BMP’s as therapeutics. Because the main role of BMP’s is bone formation, one of the most promising areas is in bone reformation after injury. BMP-7 and BMP-2 have been successfully adapted and used in combination with bone grafts during surgery, and have been extremely useful in spinal cervical fusion.
While these therapeutics are great developments, there is still much more potential because of the effects of BMP on the whole body. Currently, research is being conducted to understand how BMP-7 can be used in treating chronic kidney disease. And because of the ability to regulate neurogenesis, it is possible that BMP proteins can be used in the treatment or cure of neurodegenerative diseases such as Alzheimer's.
Overall Structure
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Draft
BMP-7 has a variety of structural characteristics. First and foremost are the two distinct domains which form the dimer. These are AC1 an AC2. They can be seen in red (AC1) and green(AC2) (). Notice how they are interacting but are not bound at the interface.
2. AA distribution
Another important attribute to view in BMP-7 is the location and number of the alpha helices. They can be seen here .
5. Other pieces (non AA)
6. Primary Structure? Secondary? Tertiary?
Binding Interactions
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Draft
BMP-7 uses two pairs of antiparallel referred as Finger 1 and Finger 2 for binding activities. The curvature of the fingers creates a site in which the α3 of the other subunit binds to stabilize the
. Free BMP-7 shows in the "wrist " and "knuckles" areas upon complexing with receptors and antagonist proteins. [A]
by BMP-7 occurs by the binding of the protein to high affinity type II receptor (at the knuckles epitope) follow by the recruitment of the low affinity type I receptor (at the "wrist " epitope). The binding causes the trans-phosphorylation of the Type I receptor at a a glycine- and serine- rich region (GS-Box) by the type II receptor kinase. Afterwards the type I receptor Ser/Thr-kinase activates leading to intracellular signaling. [C]
Bone morphogenetic proteins (BMPs)are regulated by the binding of three classes of antagonist inhibitory proteins: Noggin; the DAN family; and verterbrate Chordin and Drosophila SOG. Noggin is a homologous BMP-specific anatagonist protein found to regulate the dorsal structures in ventralized Xenopus embryos. The structure of the C-terminal half of the Noggin resembles the BMPs in that it have two pairs of antiparallel β-strands extending out from a core containing disulphides bonds. In contrast to BMP-7, binding of the monomer consists of interaction between the α4 of each monomer. When noggin binds to BMP-7, the tip of finger 1 and 2 in BMP-7 curls around the N-terminal segment of the noggin. [A]
BMP ligands have two prominent hydrophobic patches for receptor binding interfaces: convex type II and concave type I. Superposition of the noggin-BMP-7 structure show the masking of both pairs of binding epitopes. The obstruction of the type I receptor-binding occurs due to hydrophobic interactions. The hydrophobic ring of Pro 35 of the noggin inserts into the hydrophobic pocket on BMP-7 formed by Trp 52, Trp 55, Val 87, Tyr 128, and Met 131. In contrast, the type II receptor-binding is obstructed by the C-terminal half of the clip segment by the distal tip of finger 1 and by finger 2. [A]
In summary, the binding of noggin to BMP-7 consists of a hydrophobic side chain from the backbone insetred into the hydrophobic pocket of BMP followed by complementary interactions between two curved hydrophobic surfaces.
Follistatin is a proposed BMP antagonist which is present in embryonic muscle cells. The BMP antagonist enhances the BMP-7 action for muscle grwoth but it prevents the induction of apoptosis and muscle loss. The antagonist protein interacts directly with BMP but does not prevent the ligan from binding to its receptors resulting in a trimeric complex. [B]
Additional Features
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1. Mutations in NOG
a.Substitutions of six positions :Pro35Arg, Cys184Tyr, Gly189Cys, Ile220Asn, Tyr222Cys/ Tyr222Asn, Pro223Leu affect folding stability
b. Pro35Arg - decreased affinity, diminished inhibition of chondrogenesis
c. Pro35Ser- similar
2. BMP regulators evolution -BMP signalling pathway, gene duplication ligand receptor - structural homology between agonists and antagonists
Credits
Introduction - Alec
Overall Structure - William
Drug Binding Site - Felix
Additional Features - Paula
References
[A]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
[B]Floriani, C., and F. Calderazzo. "Oxygen Adducts of Schiff's Base Complexes of Cobalt Prepared in Solution." Journal of the Chemical Society A: Inorganic, Physical, Theoretical (1969): 946-53. Print.
[C]Sebald, Walter, and Thomas D. Mueller. "The Interaction of BMP-7 and ActRII Implicates a New Mode of Receptor Assembly." Trends in biochemical sciences 28.10 (2003): 518-21. Print.
