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- EMDB-44407: The Anti-Mullerian Hormone prodomain in complex with the growth f... -

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Basic information

Entry
Database: EMDB / ID: EMD-44407
TitleThe Anti-Mullerian Hormone prodomain in complex with the growth factor and 6E11 Fab in C1 symmetry
Map dataB-factor sharpened main map
Sample
  • Complex: Fab-bound AMH procomplex
    • Protein or peptide: Muellerian-inhibiting factor
    • Protein or peptide: Muellerian-inhibiting factor
    • Protein or peptide: 6E11 Antibody IgG2A Heavy Chain
    • Protein or peptide: 6E11 Antibody kappa Light Chain
KeywordsComplex / 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)
Methodsingle particle reconstruction / cryo EM / negative staining / Resolution: 3.39 Å
AuthorsHoward JA / Thompson TB
Funding support United States, 1 items
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, 2024-
Header (metadata) releaseJan 29, 2025-
Map releaseJan 29, 2025-
UpdateJan 29, 2025-
Current statusJan 29, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44407.png

Downloads & links

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Map

FileDownload / File: emd_44407.map.gz / Format: CCP4 / Size: 824 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationB-factor sharpened main map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.45 Å/pix.
x 600 pix.
= 269.7 Å		0.45 Å/pix.
x 600 pix.
= 269.7 Å		0.45 Å/pix.
x 600 pix.
= 269.7 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.4495 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.025
Minimum - Maximum-0.15009406 - 0.1978276
Average (Standard dev.)0.00005562504 (±0.00508585)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions600600600
Spacing600600600
CellA=B=C: 269.69998 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_44407_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Unsharpened main map

Fileemd_44407_additional_1.map
AnnotationUnsharpened main map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Additional map: DeepEMhancer sharpened main map using the HighRes model

Fileemd_44407_additional_2.map
AnnotationDeepEMhancer sharpened main map using the HighRes model
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Additional map: local resolution map of the main map

Fileemd_44407_additional_3.map
Annotationlocal resolution map of the main map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: unsharpened main map halfmap B

Fileemd_44407_half_map_1.map
Annotationunsharpened main map halfmap B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: unsharpened main map halfmap A

Fileemd_44407_half_map_2.map
Annotationunsharpened main map halfmap A
Projections & Slices
AxesZYX

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Sample components

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Entire : Fab-bound AMH procomplex

EntireName: Fab-bound AMH procomplex
Components
  • Complex: Fab-bound AMH procomplex
    • Protein or peptide: Muellerian-inhibiting factor
    • Protein or peptide: Muellerian-inhibiting factor
    • Protein or peptide: 6E11 Antibody IgG2A Heavy Chain
    • Protein or peptide: 6E11 Antibody kappa Light Chain

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Supramolecule #1: Fab-bound AMH procomplex

SupramoleculeName: Fab-bound AMH procomplex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: Fab generated by ficin cleavage of full-length 6E11 antibody
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 240 KDa

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Macromolecule #1: Muellerian-inhibiting factor

MacromoleculeName: Muellerian-inhibiting factor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.207711 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: LRAEEPAVGT SGLIFREDLD WPPGSPQEPL CLVALGGDSN GSSSPLRVVG ALSAYEQAFL GAVQRARWGP RDLATFGVCN TGDRQAALP SLRRLGAWLR DPGGQRLVVL HLEEVTWEPT PSLRFQEPPP GGAGPPELAL LVLYPGPGPE VTVTRAGLPG A QSLCPSRD ...String:
LRAEEPAVGT SGLIFREDLD WPPGSPQEPL CLVALGGDSN GSSSPLRVVG ALSAYEQAFL GAVQRARWGP RDLATFGVCN TGDRQAALP SLRRLGAWLR DPGGQRLVVL HLEEVTWEPT PSLRFQEPPP GGAGPPELAL LVLYPGPGPE VTVTRAGLPG A QSLCPSRD TRYLVLAVDR PAGAWRGSGL ALTLQPRGED SRLSTARLQA LLFGDDHRCF TRMTPALLLL PRSEPAPLPA HG QLDTVPF PPPRPSAELE ESPPSADPFL ETLTRLVRAL RVPPARASAP RLALDPDALA GFPQGLVNLS DPAALERLLD GEE PLLLLL RPTAATTGDP APLHDPTSAP WATALARRVA AELQAAAAEL RSLPGLPPAT APLLARLLAL CPGGPGGLGD PLRA LLLLK ALQGLRVEWR GRDPRGPGRA RR

UniProtKB: Muellerian-inhibiting factor

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Macromolecule #2: Muellerian-inhibiting factor

MacromoleculeName: Muellerian-inhibiting factor / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.659373 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString:
SAGATAADGP CALRELSVDL RAERSVLIPE TYQANNCQGV CGWPQSDRNP RYGNHVVLLL KMQARGAALA RPPCCVPTAY AGKLLISLS EERISAHHVP NMVATECGCR

UniProtKB: Muellerian-inhibiting factor

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Macromolecule #3: 6E11 Antibody IgG2A Heavy Chain

MacromoleculeName: 6E11 Antibody IgG2A Heavy Chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.079996 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: EVQLQQSGAE LVKPGASVKL SCTASGFNIK DTYMHWVKQR PEQGLEWIGR IDPANGNTIY ASKFQGKATI TADTSSNTAY MQLSSLTSG DTAVYYCALF ITTATYAMDY WGQGTSVTVS SAKTTAPSVY PLAPVCGDTT GSSVTLGCLV KGYFPEPVTL T WNSGSLSS ...String:
EVQLQQSGAE LVKPGASVKL SCTASGFNIK DTYMHWVKQR PEQGLEWIGR IDPANGNTIY ASKFQGKATI TADTSSNTAY MQLSSLTSG DTAVYYCALF ITTATYAMDY WGQGTSVTVS SAKTTAPSVY PLAPVCGDTT GSSVTLGCLV KGYFPEPVTL T WNSGSLSS GVHTFPAVLQ SDLYTLSSSV TVTSSTWPSQ SITCNVAHPA SSTKVDKKIE PRGPTIKPC

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Macromolecule #4: 6E11 Antibody kappa Light Chain

MacromoleculeName: 6E11 Antibody kappa Light Chain / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.609125 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: SIVMTQTPKF LLVSAGDRVT ITCKASQSVS NDVAWYQQKP GQSPKLLIYY ASNRYTGVPD RFTGSGYGTD FTFTISTVQA EDLAVYFCQ QDYSSLTFGA GTKLELKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDINVKWKI DGSERQNGVL N SWTDQDSK ...String:
SIVMTQTPKF LLVSAGDRVT ITCKASQSVS NDVAWYQQKP GQSPKLLIYY ASNRYTGVPD RFTGSGYGTD FTFTISTVQA EDLAVYFCQ QDYSSLTFGA GTKLELKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDINVKWKI DGSERQNGVL N SWTDQDSK DSTYSMSSTL TLTKDEYERH NSYTCEATHK TSTSPIVKSF NRNEC

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Experimental details

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Structure determination

Methodnegative staining, cryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.6 mg/mL
BufferpH: 5.5
Component:
ConcentrationNameFormula
10.0 mM2-(N-morpholino)ethanesulfonic acid
150.0 nNsodium chlorideNaCl
StainingType: NEGATIVE / Material: Uranium Formate
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 0.04 kPa / Details: 15mA current
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
DetailsSample was as indicated by negative stain. Grids were prepared immediately following SEC.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 5276 / Average electron dose: 50.5 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 0.1 mm / Nominal defocus max: 2.7 µm / Nominal defocus min: 0.6 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3486824
Startup modelType of model: NONE
Final reconstructionNumber classes used: 3 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.39 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 69149
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationNumber classes: 4 / Avg.num./class: 25000 / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-9ban:
The Anti-Mullerian Hormone prodomain in complex with the growth factor and 6E11 Fab in C1 symmetry

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