The pleiotropic cytokine Interleukin-11 (IL-11) is, amongst others, important for normal cranial bone formation. It is well-established that IL-11 signals via a signaling complex that is composed of the α-receptor (IL-11R) and a homodimer of the signal-transducing β-receptor glycoprotein 130. Formation of this signaling complex results in the activation of intracellular signalling pathways, mainly the Jak/STAT cascade.
Patients that carry certain homozygote missense mutations within the IL-11R present with symptoms of craniosynostosis, a condition that is characterized by an abnormal head shape and atypical facial features due to prematurely fused sutures. In agreement with that, also IL11R knockout mice partially show a similar head phenotype. However, the underlying molecular mechanism for these observations is so far unknown.
Detailed analysis of a patient mutation revealed that the mutated receptor shows an aberrant expression pattern. In contrast to the wildtype receptor it cannot properly reach the cell surface and is rather retained within the secretory pathway. Therefore, cells that express this receptor cannot respond to IL-11. Via molecular modelling we could show that the affected amino acid residue (arginine 296) is part of a critical conformational element in the third receptor domain and therefore crucial for protein folding and maturation. Targeted mutation of other arginine residues in this so-called arginine-tryptophan zipper showed the same characteristics as the initial mutation and further strengthens the importance of this stabilizing element. In conclusion, our results uncover the molecular reason for the phenotype observed in the human patients.