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- PDB-7mzx: AUGalpha - FAM150B - ALKL2 77-152 -

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Basic information

Entry
Database: PDB / ID: 7mzx
TitleAUGalpha - FAM150B - ALKL2 77-152
ComponentsALK and LTK ligand 2
KeywordsCYTOKINE / Anaplastic lymphoma kinase activating ligand / FAM150B / ALKL2 77-152
Function / homology
Function and homology information


positive regulation of ERK5 cascade / receptor signaling protein tyrosine kinase activator activity / transmembrane receptor protein tyrosine kinase activator activity / cytokine activity / positive regulation of neuron projection development / receptor tyrosine kinase binding / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of ERK1 and ERK2 cascade / extracellular space / extracellular region / plasma membrane
Similarity search - Function
ALK and LTK ligand 1/2 / ALK and LTK ligand 1/2
Similarity search - Domain/homology
ALK and LTK ligand 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLUTION NMR / molecular dynamics
AuthorsRossi, P. / Sowaileh, M. / Reshetnyak, A.V. / Kalodimos, C.G.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM122462 United States
CitationJournal: Nature / Year: 2021
Title: Mechanism for the activation of the anaplastic lymphoma kinase receptor.
Authors: Andrey V Reshetnyak / Paolo Rossi / Alexander G Myasnikov / Munia Sowaileh / Jyotidarsini Mohanty / Amanda Nourse / Darcie J Miller / Irit Lax / Joseph Schlessinger / Charalampos G Kalodimos /
Abstract: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that regulates important functions in the central nervous system. The ALK gene is a hotspot for chromosomal translocation events ...Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that regulates important functions in the central nervous system. The ALK gene is a hotspot for chromosomal translocation events that result in several fusion proteins that cause a variety of human malignancies. Somatic and germline gain-of-function mutations in ALK were identified in paediatric neuroblastoma. ALK is composed of an extracellular region (ECR), a single transmembrane helix and an intracellular tyrosine kinase domain. ALK is activated by the binding of ALKAL1 and ALKAL2 ligands to its ECR, but the lack of structural information for the ALK-ECR or for ALKAL ligands has limited our understanding of ALK activation. Here we used cryo-electron microscopy, nuclear magnetic resonance and X-ray crystallography to determine the atomic details of human ALK dimerization and activation by ALKAL1 and ALKAL2. Our data reveal a mechanism of RTK activation that allows dimerization by either dimeric (ALKAL2) or monomeric (ALKAL1) ligands. This mechanism is underpinned by an unusual architecture of the receptor-ligand complex. The ALK-ECR undergoes a pronounced ligand-induced rearrangement and adopts an orientation parallel to the membrane surface. This orientation is further stabilized by an interaction between the ligand and the membrane. Our findings highlight the diversity in RTK oligomerization and activation mechanisms.
History
DepositionMay 24, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 24, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 8, 2021Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Dec 15, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jun 14, 2023Group: Other / Category: pdbx_database_status / Item: _pdbx_database_status.status_code_nmr_data

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ALK and LTK ligand 2


Theoretical massNumber of molelcules
Total (without water)9,0081
Polymers9,0081
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: light scattering
TypeNameSymmetry operationNumber
identity operation1_5551
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)20 / 100target function
RepresentativeModel #1lowest energy

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Components

#1: Protein ALK and LTK ligand 2 / Augmentor alpha / AUG-alpha / Protein FAM150B


Mass: 9007.611 Da / Num. of mol.: 1 / Fragment: residues 77-152
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALKAL2, FAM150B, UNQ542/PRO1097 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q6UX46

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
111isotropic22D 1H-15N HSQC
121isotropic22D 1H-13C HSQC aliphatic
131isotropic22D 1H-13C HSQC aromatic
141isotropic23D 1H-13C NOESY
151isotropic23D 1H-15N NOESY
1141isotropic13D HNCA
1131isotropic13D HN(CA)CB
1121isotropic13D HNCO
1111isotropic13D CBCA(CO)NH
1101isotropic13D HBHA(CO)NH
191isotropic13D (H)CCH-COSY
181isotropic13D (H)CCH-TOCSY
171isotropic13D HN(CA)CO
161isotropic13D CCH TOCSY
1172isotropic13D SOFAST CCH NOESY
1162isotropic13D SOFAST HallCmHm NOESY
1152isotropic13D SOFAST HallNH NOESY

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Sample preparation

Details
TypeSolution-IDContentsDetailsLabelSolvent system
solution1300 uM [U-100% 13C; U-100% 15N] AUGalpha-FAM150B- residues 77-152, 150 mM sodium chloride, 20 mM sodium phosphate, 0.1 % sodium azide, 90% H2O/10% D2ODouble labeled 13C,15N13C15N_sample90% H2O/10% D2O
solution2300 uM U-15N, U-1H,13C_CH3_AILMTV AUGalpha-FAM150B- residues 77-152, 150 mM sodium chloride, 20 mM sodium phosphate, 0.1 % sodium azide, 90% H2O/10% D2OU-15N, U-1H,13C_CH3_AILMTVMethyl_N15_sample90% H2O/10% D2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
300 uMAUGalpha-FAM150B- residues 77-152[U-100% 13C; U-100% 15N]1
150 mMsodium chloridenatural abundance1
20 mMsodium phosphatenatural abundance1
0.1 %sodium azidenatural abundance1
300 uMAUGalpha-FAM150B- residues 77-152U-15N, U-1H,13C_CH3_AILMTV2
150 mMsodium chloridenatural abundance2
20 mMsodium phosphatenatural abundance2
0.1 %sodium azidenatural abundance2
Sample conditionsIonic strength: 170 mM / Label: conditions_1 / pH: 7.0 / Pressure: 1 atm / Temperature: 298 K

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NMR measurement

NMR spectrometer
TypeManufacturerModelField strength (MHz)Spectrometer-ID
Bruker AVANCE NEOBrukerAVANCE NEO7001
Bruker AVANCE NEOBrukerAVANCE NEO8502

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Processing

NMR software
NameVersionDeveloperClassification
CNSBrunger, Adams, Clore, Gros, Nilges and Readrefinement
CYANA3.98Guntert, Mumenthaler and Wuthrichstructure calculation
PINEBahrami, Markley, Assadi, and Eghbalniachemical shift assignment
NMRFAM-SPARKYLee, Markley et. al.peak picking
TopSpin4.06Bruker Biospincollection
NMRPipeDelaglio, Grzesiek, Vuister, Zhu, Pfeifer and Baxprocessing
PSVSBhattacharya and Montelionerefinement
TALOS-NShen and Baxgeometry optimization
PdbStatTejero and Montelionerefinement
RefinementMethod: molecular dynamics / Software ordinal: 1 / Details: Restrained MD in explicit H2O bath
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: target function / Conformers calculated total number: 100 / Conformers submitted total number: 20

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