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- PDB-7mzz: AUGbeta - FAM150A - ALKL1 60-128 -

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Basic information

Entry
Database: PDB / ID: 7mzz
TitleAUGbeta - FAM150A - ALKL1 60-128
ComponentsALK and LTK ligand 1
KeywordsCYTOKINE / Anaplastic lymphoma kinase (ALK) activating ligand / FAM150B / ALKL2 77-152
Function / homology
Function and homology information


positive regulation of ERK5 cascade / receptor signaling protein tyrosine kinase activator activity / Signaling by LTK / Signaling by ALK / transmembrane receptor protein tyrosine kinase activator activity / cell surface receptor protein tyrosine kinase signaling pathway / cytokine activity / receptor tyrosine kinase binding / positive regulation of neuron projection development / positive regulation of ERK1 and ERK2 cascade ...positive regulation of ERK5 cascade / receptor signaling protein tyrosine kinase activator activity / Signaling by LTK / Signaling by ALK / transmembrane receptor protein tyrosine kinase activator activity / cell surface receptor protein tyrosine kinase signaling pathway / cytokine activity / receptor tyrosine kinase binding / positive regulation of neuron projection development / 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 1
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
Revision 1.4Nov 6, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ALK and LTK ligand 1


Theoretical massNumber of molelcules
Total (without water)8,1871
Polymers8,1871
Non-polymers00
Water00
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 1 / Augmentor beta / AUG-beta / Protein FAM150A


Mass: 8187.402 Da / Num. of mol.: 1 / Fragment: residues 60-129
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALKAL1, FAM150A, UNQ9433/PRO34745 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q6UXT8
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
111isotropic12D 1H-15N HSQC
121isotropic22D 1H-13C HSQC
131isotropic22D 1H-13C HSQC aromatic
142isotropic12D 2D 1H-13C HMQC
151isotropic13D 1H-13C NOESY
1171isotropic23D 1H-15N NOESY
1161isotropic23D 1H-13C NOESY aromatic
1151isotropic23D HCACO
1141isotropic23D HN(CA)CB
1131isotropic23D HNCO
1121isotropic23D HBHA(CO)NH
1111isotropic23D CBCA(CO)NH
1101isotropic23D CCH TOCSY
191isotropic23D (H)CCH-COSY
182isotropic13D sfCCH NOESY
172isotropic13D sfHallCmHm NOESY

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Sample preparation

Details
TypeSolution-IDContentsDetailsLabelSolvent system
solution1300 uM [U-10% 13C; U-100% 15N] AUGbeta-FAM150A-ALKL1 residues 60-129, 0.1 % sodium azide, 20 mM sodium phosphate, 150 mM sodium chloride, 90% H2O/10% D2OU-100% 13C,15N13C_15N_sample90% H2O/10% D2O
solution2300 uM [U-10% 13C; U-100% 15N AILTV methyl sample] AUGbeta-FAM150A-ALKL1 residues 60-129, 0.1 % sodium azide, 20 mM sodium phosphate, 150 mM sodium chloride, 90% H2O/10% D2OU-100% 15N, U-100% 1H,13C AILTV methyl15N_1H,13H_AILTV_methyl_sample90% H2O/10% D2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
300 uMAUGbeta-FAM150A-ALKL1 residues 60-129[U-10% 13C; U-100% 15N]1
0.1 %sodium azidenatural abundance1
20 mMsodium phosphatenatural abundance1
150 mMsodium chloridenatural abundance1
300 uMAUGbeta-FAM150A-ALKL1 residues 60-129[U-10% 13C; U-100% 15N AILTV methyl sample]2
0.1 %sodium azidenatural abundance2
20 mMsodium phosphatenatural abundance2
150 mMsodium chloridenatural abundance2
Sample conditionsIonic strength: 170 mM / Label: conditions_1 / pH: 7 / Pressure: 1 atm / Temperature: 298 K

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NMR measurement

NMR spectrometer
TypeManufacturerModelField strength (MHz)Spectrometer-ID
Bruker AVANCE NEOBrukerAVANCE NEO8501
Bruker AVANCE NEOBrukerAVANCE NEO7002

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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-SPARKYW.Leepeak picking
TopSpin4.06Bruker Biospincollection
TALOS-NShen and Baxgeometry optimization
NMRPipeDelaglio, Grzesiek, Vuister, Zhu, Pfeifer and Baxprocessing
PdbStatTejero and Montelioneprocessing
PSVSBhattacharya and Montelioneprocessing
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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