Abstract:
:Ciliary neurotrophic factor (CNTF) receptor controls a pathway supporting the differentiation and survival of a wide range of neural cell types during development and in adulthood. Cardiotrophin-like cytokine (CLC)-cytokine-like factor 1 (CLF) composite cytokine is a second ligand for the CNTF alpha-component receptor (CNTFRalpha). This composite cytokine is built on the structural model of IL-12, with a complex formed by a four-helix bundle type I cytokine, CLC (also referred to as CLCF1), bound to a soluble receptor subunit, CLF (also known as CRLF1). We have reported mutations in the chaperone soluble receptor CLF, causing cold-induced sweating syndrome (CISS). In this study, we studied the CLC-mutated alleles in a patient suffering from a similar disease. This patient was compound heterozygous for two different CLC mutations. The first allele was inactivated by a stop codon at position 107 (Y107X). In the second allele, a R197L mutation in the CLC-predicted binding site to the CNTFRalpha was detected. Functional analysis of the mutated protein revealed an incapacity for R197L CLC to bind to CNTFRalpha and activate the subsequent signaling events. Structural and docking interaction studies showed that the R197L substitution destabilized the contact site between CLC and CNTFRalpha.
journal_name
Proc Natl Acad Sci U S Aauthors
Rousseau F,Gauchat JF,McLeod JG,Chevalier S,Guillet C,Guilhot F,Cognet I,Froger J,Hahn AF,Knappskog PM,Gascan H,Boman Hdoi
10.1073/pnas.0509598103subject
Has Abstractpub_date
2006-06-27 00:00:00pages
10068-73issue
26eissn
0027-8424issn
1091-6490pii
0509598103journal_volume
103pub_type
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