Structural perspective of BMP ligands and signaling

Gipson, Gregory R.; Goebel, Erich J; Hart, Kaitlin; Kappes, Emily C; Kattamuri, Chandramohan; McCoy, Jason C.; Thompson, Thomas B.

doi:10.1016/j.bone.2020.115549

Cited by 40 publications

(38 citation statements)

References 202 publications

(329 reference statements)

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“…Previous structural studies of TGF-β ligands and receptors have provided a good understanding for how different type II receptors bind and engage different ligands. In general, ligands adopt a very similar shape in which sequence differences paired with minor structural differences account for the specificity of ligand-type II pairings (7,24). Now having the structures of AMH and AMHR2, we wanted to perform a cross-comparison to other ligands in the family as well as other type II TGF-β receptors.…”

Section: Resultsmentioning

confidence: 99%

Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-β family

Hart

Stocker

Nagykery

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Anti-Müllerian hormone (AMH), or Müllerian-inhibiting substance, is a protein hormone that promotes Müllerian duct regression during male fetal sexual differentiation and regulation of folliculogenesis in women. AMH is a member of the transforming growth factor beta (TGF-β) family, which has evolved to signal through its own dedicated type II receptor, AMH receptor type II (AMHR2). Structures of other TGF-β family members have revealed how ligands infer specificity for their cognate receptors; however, it is unknown how AMH binds AMHR2 at the molecular level. Therefore, in this study, we solved the X-ray crystal structure of AMH bound to the extracellular domain of AMHR2 to a resolution of 2.6Å. The structure reveals that while AMH binds AMHR2 in a similar location to Activin and BMP ligand binding to their type II receptors, differences in both AMH and AMHR2 account for a highly specific interaction. Furthermore, using an AMH responsive cell-based luciferase assay, we show that a conformation in finger 1 of AMHR2 and a salt bridge formed by K534 on AMH and D81/E84 of AMHR2 are key to the AMH/AMHR2 interaction. Overall, our study highlights how AMH engages AMHR2 using a modified paradigm of receptor binding facilitated by modifications to the three-finger toxin fold of AMHR2. Furthermore, understanding these elements contributing to the specificity of binding will help in the design of agonists or antagonists or the selection of antibody therapies.

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Section: Resultsmentioning

confidence: 99%

Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-β family

Hart

Stocker

Nagykery

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…Inhibitory (I)-Smads block TGFb signaling by either preventing R-Smad phosphorylation by TGFR2 or preventing binding of Co-Smad to phospho-R-Smad. FK-506 binding protein 1A (FKBP12) binds to TGFR1 and prevents phosphorylation of TGFR1 by TGFR2 (141,146). BMP and activin membrane bound inhibitor (BAMBI) acts as a TGFR1 pseudo receptor, as it binds ligand, but lacks the protein kinase domain for signal transduction.…”

Section: Transforming Factor B/activin Signalingmentioning

confidence: 99%

Signaling Pathways That Regulate the Crustacean Molting Gland

Mykles

2021

Front. Endocrinol.

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A pair of Y-organs (YOs) are the molting glands of decapod crustaceans. They synthesize and secrete steroid molting hormones (ecdysteroids) and their activity is controlled by external and internal signals. The YO transitions through four physiological states over the molt cycle, which are mediated by molt-inhibiting hormone (MIH; basal state), mechanistic Target of Rapamycin Complex 1 (mTORC1; activated state), Transforming Growth Factor-β (TGFβ)/Activin (committed state), and ecdysteroid (repressed state) signaling pathways. MIH, produced in the eyestalk X-organ/sinus gland complex, inhibits the synthesis of ecdysteroids. A model for MIH signaling is organized into a cAMP/Ca2+-dependent triggering phase and a nitric oxide/cGMP-dependent summation phase, which maintains the YO in the basal state during intermolt. A reduction in MIH release triggers YO activation, which requires mTORC1-dependent protein synthesis, followed by mTORC1-dependent gene expression. TGFβ/Activin signaling is required for YO commitment in mid-premolt. The YO transcriptome has 878 unique contigs assigned to 23 KEGG signaling pathways, 478 of which are differentially expressed over the molt cycle. Ninety-nine contigs encode G protein-coupled receptors (GPCRs), 65 of which bind a variety of neuropeptides and biogenic amines. Among these are putative receptors for MIH/crustacean hyperglycemic hormone neuropeptides, corazonin, relaxin, serotonin, octopamine, dopamine, allatostatins, Bursicon, ecdysis-triggering hormone (ETH), CCHamide, FMRFamide, and proctolin. Contigs encoding receptor tyrosine kinase insulin-like receptor, epidermal growth factor (EGF) receptor, and fibroblast growth factor (FGF) receptor and ligands EGF and FGF suggest that the YO is positively regulated by insulin-like peptides and growth factors. Future research should focus on the interactions of signaling pathways that integrate physiological status with environmental cues for molt control.

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“…ALK2 was originally identified as a cell-surface protein interacting with TGF-β and activin A [ 64 , 65 ]. Subsequently, ALK2 was found to bind to and signal for BMPs (such as BMP-5/6/7), thereby triggering SMAD1/5/8 activation [ 66 , 67 , 68 , 69 ]. Several consecutive studies confirmed that ALK2 forms a non signalling complex upon binding to activin A and type II receptors [ 30 , 70 ], and that activin and BMP7 compete for type II receptor binding [ 29 ].…”

Section: Aberrant Tgf-β Signalling Underlies Fopmentioning

confidence: 99%

Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva

et al. 2021

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Fibrodysplasia ossificans progressiva (FOP) is an ultrarare congenital disease that progresses through intermittent episodes of bone formation at ectopic sites. FOP patients carry heterozygous gene point mutations in activin A receptor type I ACVR1, encoding the bone morphogenetic protein (BMP) type I serine/threonine kinase receptor ALK2, termed activin receptor-like kinase (ALK)2. The mutant ALK2 displays neofunctional responses to activin, a closely related BMP cytokine that normally inhibits regular bone formation. Moreover, the mutant ALK2 becomes hypersensitive to BMPs. Both these activities contribute to enhanced ALK2 signalling and endochondral bone formation in connective tissue. Being a receptor with an extracellular ligand-binding domain and intrinsic intracellular kinase activity, the mutant ALK2 is a druggable target. Although there is no approved cure for FOP yet, a number of clinical trials have been recently initiated, aiming to identify a safe and effective treatment for FOP. Among other targeted approaches, several repurposed drugs have shown promising results. In this review, we describe the molecular mechanisms underlying ALK2 mutation-induced aberrant signalling and ectopic bone formation. In addition, we recapitulate existing in vitro models to screen for novel compounds with a potential application in FOP. We summarize existing therapeutic alternatives and focus on repositioned drugs in FOP, at preclinical and clinical stages.

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Structural perspective of BMP ligands and signaling

Cited by 40 publications

References 202 publications

Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-β family

Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-β family

Signaling Pathways That Regulate the Crustacean Molting Gland

Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva

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