PDBsum entry 5e4e

Signaling protein

PDB id: 5e4e

Contents

Protein chains

111 a.a.

183 a.a.

303 a.a.

Ligands

SO4 ×7

NAG ×2

PDB id:

5e4e

Name:

Signaling protein

Title:

Engineered interleukin-13 bound to receptor

Structure:

Interleukin-13. Chain: a. Fragment: unp residues 34-146. Synonym: il-13. Engineered: yes. Mutation: yes. Interleukin-4 receptor subunit alpha. Chain: b. Fragment: unp residues 26-228.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: il13, nc30. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Gene: il4r, il4ra, 582j2.1. Gene: il13ra1, il13r, il13ra. Expression_system_taxid: 7111

Resolution:

3.00Å R-factor: 0.237 R-free: 0.289

Authors:

I.Moraga,C.Thomas,K.M.Jude,K.C.Garcia

Key ref:

I.Moraga et al. (2015). Instructive roles for cytokine-receptor binding parameters in determining signaling and functional potency. Sci Signal, 8, ra114. PubMed id: 26554818 DOI: 10.1126/scisignal.aab2677

Date:

05-Oct-15 Release date: 02-Dec-15

Protein chain

P35225  (IL13_HUMAN) -  Interleukin-13 from Homo sapiens

Seq: 146 a.a.

Struc: 111 a.a.*

Protein chain

P24394  (IL4RA_HUMAN) -  Interleukin-4 receptor subunit alpha from Homo sapiens

Seq: 825 a.a.

Struc: 183 a.a.

Protein chain

P78552  (I13R1_HUMAN) -  Interleukin-13 receptor subunit alpha-1 from Homo sapiens

Seq: 427 a.a.

Struc: 303 a.a.

* PDB and UniProt seqs differ at 8 residue positions (black crosses)

DOI no: 10.1126/scisignal.aab2677

Sci Signal 8:ra114 (2015)

PubMed id: 26554818

Instructive roles for cytokine-receptor binding parameters in determining signaling and functional potency.

I.Moraga, D.Richter, S.Wilmes, H.Winkelmann, K.Jude, C.Thomas, M.M.Suhoski, E.G.Engleman, J.Piehler, K.C.Garcia.

ABSTRACT

Cytokines dimerize cell surface receptors to activate signaling and regulate many facets of the immune response. Many cytokines have pleiotropic effects, inducing a spectrum of redundant and distinct effects on different cell types. This pleiotropy has hampered cytokine-based therapies, and the high doses required for treatment often lead to off-target effects, highlighting the need for a more detailed understanding of the parameters controlling cytokine-induced signaling and bioactivities. Using the prototypical cytokine interleukin-13 (IL-13), we explored the interrelationships between receptor binding and a wide range of downstream cellular responses. We applied structure-based engineering to generate IL-13 variants that covered a spectrum of binding strengths for the receptor subunit IL-13Rα1. Engineered IL-13 variants representing a broad range of affinities for the receptor exhibited similar potencies in stimulating the phosphorylation of STAT6 (signal transducer and activator of transcription 6). Delays in the phosphorylation and nuclear translocation of STAT6 were only apparent for those IL-13 variants with markedly reduced affinities for the receptor. From these data, we developed a mechanistic model that quantitatively reproduced the kinetics of STAT6 phosphorylation for the entire spectrum of binding affinities. Receptor endocytosis played a key role in modulating STAT6 activation, whereas the lifetime of receptor-ligand complexes at the plasma membrane determined the potency of the variant for inducing more distal responses. This complex interrelationship between extracellular ligand binding and receptor function provides the foundation for new mechanism-based strategies that determine the optimal cytokine dose to enhance therapeutic efficacy.