Molecular Dissection of Human Interleukin-31-mediated Signal Transduction Through Site-directed Mutagenesis

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2009 Nov 19

PMID 19920145

Citations 6

Authors

Sabine Le Saux

Francois Rousseau

Fabien Barbier

Elisa Ravon

Linda Grimaud

Yannic Danger

Josy Froger

Sylvie Chevalier

Hugues Gascan

Affiliations

Soon will be listed here.

Abstract

Interleukin (IL)-31 is a recently described cytokine, preferentially produced by T helper 2 lymphocytes and associated with skin diseases, such as atopic dermatitis. IL-31 is a member of the four alpha-helix bundle cytokine family and is related to the IL-6 subgroup. Its heterodimeric membrane receptor is composed of the gp130-like receptor (GPL) subunit associated to the oncostatin M receptor subunit. We identified critical amino acids implicated in the ligand receptor interaction by computational analysis combined with site-directed mutagenesis. Six IL-31 residues selected for their putative involvement in cytokine receptor contact sites were alanine-substituted, and the corresponding proteins were expressed in mammalian and bacterial systems. Biochemical, membrane binding, cell signaling, and cell proliferation analyses showed that mutation E44A, E106A, or H110A abolished IL-31 binding to GPL and the subsequent signaling events. A second ligand receptor-binding site involved Lys(134), with alanine substitution leading to a protein that still binds GPL, but is unable to recruit the second receptor subunit and the subsequent signaling pathways. The results indicate that IL-31 recognizes its receptor complex through two different binding sites, and we propose a three-dimensional model for IL-31.

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