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- PDB-9bao: The Anti-Mullerian Hormone prodomain in complex with the growth f... -

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Basic information

Entry
Database: PDB / ID: 9bao
TitleThe Anti-Mullerian Hormone prodomain in complex with the growth factor and 6E11 Fab in C2 symmetry
Components
  • (Muellerian-inhibiting factor) x 2
  • 6E11 Antibody IgG2A Heavy Chain
  • 6E11 Antibody kappa Light Chain
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / Complex / TGF-beta prodomain / Signaling ligand / Helical bundle / SIGNALING PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


preantral ovarian follicle growth / anti-Mullerian hormone receptor signaling pathway / negative regulation of ovarian follicle development / gonadal mesoderm development / Mullerian duct regression / urogenital system development / sex determination / Transcriptional regulation of testis differentiation / sex differentiation / Leydig cell differentiation ...preantral ovarian follicle growth / anti-Mullerian hormone receptor signaling pathway / negative regulation of ovarian follicle development / gonadal mesoderm development / Mullerian duct regression / urogenital system development / sex determination / Transcriptional regulation of testis differentiation / sex differentiation / Leydig cell differentiation / type II transforming growth factor beta receptor binding / Signaling by BMP / positive regulation of SMAD protein signal transduction / ovarian follicle development / growth factor activity / hormone activity / cell-cell signaling / response to xenobiotic stimulus / signaling receptor binding / positive regulation of gene expression / extracellular space / extracellular region
Similarity search - Function
Anti-Mullerian hormone, N-terminal / Muellerian-inhibiting factor / Anti-Mullerian hormone, N terminal region / Transforming growth factor beta, conserved site / TGF-beta family signature. / Transforming growth factor-beta (TGF-beta) family / Transforming growth factor-beta, C-terminal / Transforming growth factor beta like domain / TGF-beta family profile. / Cystine-knot cytokine
Similarity search - Domain/homology
Muellerian-inhibiting factor
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / negative staining / cryo EM / Resolution: 3.2 Å
AuthorsHoward, J.A. / Thompson, T.B.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)HD105818 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: A divergent two-domain structure of the anti-Müllerian hormone prodomain.
Authors: James A Howard / Lucija Hok / Richard L Cate / Nathaniel J Sanford / Kaitlin N Hart / Edmund A E Leach / Alena S Bruening / Nicholas Nagykery / Patricia K Donahoe / David Pépin / Thomas B Thompson /
Abstract: TGFβ family ligands are synthesized as precursors consisting of an N-terminal prodomain and C-terminal growth factor (GF) signaling domain. After proteolytic processing, the prodomain typically ...TGFβ family ligands are synthesized as precursors consisting of an N-terminal prodomain and C-terminal growth factor (GF) signaling domain. After proteolytic processing, the prodomain typically remains noncovalently associated with the GF, sometimes forming a high-affinity latent procomplex that requires activation. For the TGFβ family ligand anti-Müllerian hormone (AMH), the prodomain maintains a high-affinity interaction with its GF that does not render it latent. While the prodomain can be displaced by the type II receptor, AMHR2, the nature of the GF:prodomain interaction and the mechanism of prodomain displacement by AMHR2 are currently unknown. We show here that the AMH prodomain exhibits an atypical two-domain structure, containing a dimerizing and a GF-binding domain connected through a flexible linker. Cryo-EM and genomic analyses show that the distinctive GF-binding domain, the result of an exon insertion 450 Mya, comprises a helical bundle and a belt-like structure which interact with the GF at the type II and I receptor binding sites, respectively. The dimerizing domain, which adopts a TGFβ-like propeptide fold, covalently connects two prodomains through intermolecular disulfide bonds. Disease mutations map to both the GF-binding and dimerization domains. Our results support a model where AMHR2 displaces the helical bundle and induces a conformational change in the GF, followed by release of the prodomain and engagement of the type I receptor. Collectively, this study shows that the AMH prodomain has evolved an atypical binding interaction with the GF that favors, without disrupting signaling, the maintenance of a noncovalent complex until receptors are engaged.
History
DepositionApr 4, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 29, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Muellerian-inhibiting factor
B: Muellerian-inhibiting factor
C: Muellerian-inhibiting factor
D: Muellerian-inhibiting factor
E: 6E11 Antibody IgG2A Heavy Chain
F: 6E11 Antibody kappa Light Chain
G: 6E11 Antibody IgG2A Heavy Chain
H: 6E11 Antibody kappa Light Chain


Theoretical massNumber of molelcules
Total (without water)209,1128
Polymers209,1128
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Muellerian-inhibiting factor / Anti-Muellerian hormone / AMH / Muellerian-inhibiting substance / MIS


Mass: 45207.711 Da / Num. of mol.: 2 / Fragment: prodomain (UNP residues 25-451) / Mutation: Q450R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AMH, MIF / Production host: Homo sapiens (human) / References: UniProt: P03971
#2: Protein Muellerian-inhibiting factor / Anti-Muellerian hormone / AMH / Muellerian-inhibiting substance / MIS


Mass: 11659.373 Da / Num. of mol.: 2 / Fragment: growth factor domain (UNP residues 459-560) / Mutation: V565A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AMH, MIF / Production host: Homo sapiens (human) / References: UniProt: P03971
#3: Antibody 6E11 Antibody IgG2A Heavy Chain


Mass: 24079.996 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): B-cell Hybridoma / Production host: Mus musculus (house mouse)
#4: Antibody 6E11 Antibody kappa Light Chain


Mass: 23609.125 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): B-cell Hybridoma / Production host: Mus musculus (house mouse)
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Fab-bound AMH procomplex / Type: COMPLEX
Details: Fab generated by ficin cleavage of full-length 6E11 antibody
Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightValue: .24 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 5.5
Buffer component
IDConc.NameFormulaBuffer-ID
110 mM2-(N-morpholino)ethanesulfonic acid1
2150 nNsodium chlorideNaCl1
SpecimenConc.: 0.6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: YES / Vitrification applied: YES
Details: Sample was as indicated by negative stain. Grids were prepared immediately following SEC.
EM stainingType: NEGATIVE / Material: Uranium Formate
Specimen supportDetails: 15mA current / Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 81000 X / Nominal defocus max: 2700 nm / Nominal defocus min: 600 nm / Cs: 0.1 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 5276

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2EPUimage acquisition
4cryoSPARCCTF correction
7ISOLDEmodel fitting
9PHENIXmodel refinement
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 3486824
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 69149 / Num. of class averages: 3 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: REAL
Atomic model buildingSource name: AlphaFold / Type: in silico model

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