Structural and Functional Attributes of the Interleukin-36 Receptor.
Signal transduction by the IL-36 receptor (IL-36R) is linked to several human diseases. However, the structure and function of the IL-36R is not well understood. A molecular model of the IL-36R complex was generated and a cell-based reporter assay was established to assess the signal transduction of recombinant subunits of the IL-36R. Mutational analyses and functional assays have identified residues of the receptor subunit IL-1Rrp2 needed for cytokine recognition, stable protein expression, disulfide bond formation and glycosylation that are critical for signal transduction. We also observed that, overexpression of ectodomain (ECD) of Il-1Rrp2 or IL-1RAcP exhibited dominant-negative effect on IL-36R signaling. The presence of IL-36 cytokine significantly increased the interaction of IL-1Rrp2 ECD with the co-receptor IL-1RAcP. Finally, we found that single nucleotide polymorphism A471T in the Toll-interleukin 1 receptor domain (TIR) of the IL-1Rrp2 that is present in ∼2% of the human population, down-regulated IL-36R signaling by a decrease of interaction with IL-1RAcP.
From the Departments of Molecular and Cellular Biochemistry and.
Guanghui
G
Yi
Environmental Health, School of Public Health, Indiana University, Bloomington, Indiana 47405 and.
Joel A
JA
Ybe
From the Departments of Molecular and Cellular Biochemistry and.
Siddhartha S
SS
Saha
Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877.
Gary
G
Caviness
Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877.
Ernest
E
Raymond
Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877.
Rajkumar
R
Ganesan
Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877.
M Lamine
ML
Mbow
From the Departments of Molecular and Cellular Biochemistry and ckao@indiana.edu.
C Cheng
CC
Kao
D057809:HEK293 Cells; D006801:Humans; D053577:Interleukin-1 Receptor Accessory Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053727:Interleukin-18 Receptor alpha Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D000072417:Protein Domains; D015398:Signal Transduction; D013329:Structure-Activity Relationship
C508572:IL18R1 protein, human; C507765:IL1RAP protein, human; D053577:Interleukin-1 Receptor Accessory Protein; D053727:Interleukin-18 Receptor alpha Subunit
cytokine; immunology; membrane protein; psoriasis; receptor structure-function; signal transduction