SASDB99: Extracellular assembly of the human TSLP:TSLPR:IL-7Ralpha complex

Basic information

• Entry: Database: SASBDB / ID: SASDB99

Sample

Extracellular assembly of the human TSLP:TSLPR:IL-7Ralpha complex

• Thymic stromal lymphopoietin (protein), TSLP, Homo sapiens
• Interleukin-7 receptor subunit alpha (protein), IL-7Rα, Homo sapiens
• Cytokine receptor-like factor 2 (protein), TSLPR, Homo sapiens

Function / homology

Function:

positive regulation of chemokine (C-C motif) ligand 1 production / positive regulation of granulocyte colony-stimulating factor production / interleukin-7 receptor activity / interleukin-7 receptor binding / positive regulation of mast cell activation / positive regulation of receptor signaling pathway via STAT / negative regulation of T cell mediated cytotoxicity / regulation of DNA recombination / positive regulation of cytokine-mediated signaling pathway / positive regulation of T cell differentiation in thymus / positive regulation of interleukin-13 production / positive regulation of interleukin-5 production / negative regulation of T cell apoptotic process / cytokine receptor activity / regulation of cell size / cytokine binding / B cell proliferation / T cell homeostasis / positive regulation of interleukin-10 production / B cell homeostasis / hemopoiesis / defense response to fungus / lymph node development / positive regulation of chemokine production / positive regulation of tyrosine phosphorylation of STAT protein / Interleukin-7 signaling / cytokine activity / antigen binding / positive regulation of receptor signaling pathway via JAK-STAT / clathrin-coated endocytic vesicle membrane / cell morphogenesis / T cell mediated cytotoxicity / cytokine-mediated signaling pathway / positive regulation of inflammatory response / antimicrobial humoral immune response mediated by antimicrobial peptide / positive regulation of interleukin-6 production / Cargo recognition for clathrin-mediated endocytosis / Clathrin-mediated endocytosis / gene expression / T cell differentiation in thymus / defense response to Gram-negative bacterium / cell surface receptor signaling pathway / receptor complex / defense response to Gram-positive bacterium / immune response / external side of plasma membrane / positive regulation of cell population proliferation / positive regulation of gene expression / negative regulation of apoptotic process / signal transduction / extracellular space / extracellular region / nucleoplasm / plasma membrane / cytosol

Domain/homology:

Thymic stromal lymphopoietin / Thymic stromal lymphopoietin superfamily / Thymic stromal lymphopoietin / IL-7Ralpha, fibronectin type III domain / Fibronectin type III domain / : / : / Cytokine receptor-like factor 2-like, D1 domain / Cytokine receptor-like factor 2-like, D2 domain / Short hematopoietin receptor family 1 signature. / Short hematopoietin receptor, family 1, conserved site / Fibronectin type III domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Immunoglobulin-like fold

Component:

Interleukin-7 receptor subunit alpha / Thymic stromal lymphopoietin / Cytokine receptor-like factor 2

• Biological species: Homo sapiens (human)
• Citation: Journal: Nat Commun / Year: 2017; Title: Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma.; Authors: Kenneth Verstraete / Frank Peelman / Harald Braun / Juan Lopez / Dries Van Rompaey / Ann Dansercoer / Isabel Vandenberghe / Kris Pauwels / Jan Tavernier / Bart N Lambrecht / Hamida Hammad / Hans De Winter / Rudi Beyaert / Guy Lippens / Savvas N Savvides / ; Abstract: The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is pivotal to the pathophysiology of widespread allergic diseases mediated by type 2 helper T cell (Th2) responses, including asthma and atopic dermatitis. The emergence of human TSLP as a clinical target against asthma calls for maximally harnessing its therapeutic potential via structural and mechanistic considerations. Here we employ an integrative experimental approach focusing on productive and antagonized TSLP complexes and free cytokine. We reveal how cognate receptor TSLPR allosterically activates TSLP to potentiate the recruitment of the shared interleukin 7 receptor α-chain (IL-7Rα) by leveraging the flexibility, conformational heterogeneity and electrostatics of the cytokine. We further show that the monoclonal antibody Tezepelumab partly exploits these principles to neutralize TSLP activity. Finally, we introduce a fusion protein comprising a tandem of the TSLPR and IL-7Rα extracellular domains, which harnesses the mechanistic intricacies of the TSLP-driven receptor complex to manifest high antagonistic potency.

Contact author

• Kenneth Verstraete (Ghent University)

Models

• Model #1113: ; Type: atomic / Software: AllosMod-FoXS (005772e) / Radius of dummy atoms: 1.90 A / Symmetry: P1 / Chi-square value: 5.80855488685; Search similar-shape structures of this assembly by Omokage search (details)

Sample

• Sample: Name: Extracellular assembly of the human TSLP:TSLPR:IL-7Ralpha complex; Entity id: 580 / 581 / 582
• Buffer: Name: 10 mM Hepes, 150 mM NaCl / pH: 7.4

Entity #580

Name: TSLP / Type: protein / Description: Thymic stromal lymphopoietin / Formula weight: 14.618 / Num. of mol.: 1 / Source: Homo sapiens / References: UniProt: Q969D9
Sequence:

GSHMYDFTNC DFEKIKAAYL STISKDLITY MSGTKSTEFN NTVSCSNRPH CLTEIQSLTF NPTAGCASLA KEMFAMKTKA ALAIWCPGYS ETQINATQAM KKVTTNKCLE QVSQLQGLWR RFNRPLLKQQ

Entity #581

Name: IL-7Rα / Type: protein / Description: Interleukin-7 receptor subunit alpha / Formula weight: 25.672 / Num. of mol.: 1 / Source: Homo sapiens / References: UniProt: P16871
Sequence:

GSHMESGYAQ NGDLEDAELD DYSFSCYSQL EVNGSQHSLT CAFEDPDVNI TNLEFEICGA LVEVKCLNFR KLQEIYFIET KKFLLIGKSN ICVKVGEKSL TCKKIDLTTI VKPEAPFDLS VVYREGANDF VVTFNTSHLQ KKYVKVLMHD VAYRQEKDEN KWTHVNLSST KLTLLQRKLQ PAAMYEIKVR SIPDHYFKGF WSEWSPSYYF RTPEINNSSG EMD

Entity #582

Name: TSLPR / Type: protein / Description: Cytokine receptor-like factor 2 / Formula weight: 24.059 / Num. of mol.: 1 / Source: Homo sapiens / References: UniProt: Q9HC73
Sequence:

GAAEGVQIQI IYFNLETVQV TWQASKYSRT NLTFHYRFNG DEAYDQCTNY LLQEGHTSGC LLDAEQRDDI LYFSIRNGTH PVFTASRWMV YYLKPSSPKH VRFSWHQDAV TVTCSDLSYG DLLYEVQYRS PFDTEWQSKQ ENTCQVTIEG LDAEKCYSFW VRVKAMEDVY GPDTYPSDWS EVTCWQRGEI RDACAETGTK HHHHHH

Experimental information

• Beam: Instrument name: SOLEIL SWING / City: Saint-Aubin / 国: France / Type of source: X-ray synchrotron / Wavelength: 0.103 Å
• Detector: Name: AVIEX / Type: CCD

Scan

Title: TSLPΔ127-131:TSLPRN47Q:IL-7R complex / Measurement date: Apr 8, 2016 / Cell temperature: 15 °C / Exposure time: 1 sec. / Number of frames: 255 / Unit: 1/A /

	Min	Max
Q	0.0097	0.6139

Distance distribution function P(R)

Sofotware P(R): GNOM 5.0 / Number of points: 430 /

	Min	Max
Q	0.011927	0.25541
P(R) point	1	430
R	0	103.2

Result

Type of curve: other

	Experimental	Standard	Porod
MW	64.3 kDa	58.7 kDa	61.3 kDa
Volume	-	-	98.02 nm3

	P(R)	P(R) error	Guinier
Forward scattering, I0	0.0533	1.986E-5	0.053
Radius of gyration, Rg	3.135 nm	0.002	3.12 nm

	Min	Max
D	-	10.32
Guinier point	5	57