IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis.
Previously, human genetics-based approaches allowed us to show that mutations in the IL-1 receptor accessory protein-like gene (IL1RAPL) are responsible for a non-specific form of X-linked mental retardation. This gene encodes a predicted protein of 696 amino acids that belongs to a novel class of the IL-1/Toll receptor family. In addition to the extracellular portion consisting of three Ig-like domains and the intracellular TIR domain characteristic of the IL-1/Toll receptor family, IL1RAPL contains a specific 150 amino acid carboxy terminus that has no significant homology with any protein of known function. In order to begin to elucidate the function of this IL-1/Toll receptor-like protein, we have assessed the effect of recombinant IL1RAPL on the binding affinity of type I IL-1R for its ligands IL-1alpha and beta and searched for proteins interacting with the specific carboxy terminus domain of IL1RAPL. Our results show that IL1RAPL is not a protein receptor for IL-1. In addition we present here the identification of Neuronal Calcium Sensor-1 (NCS-1) as an IL1RAPL interactor. Remarkably, although NCS-1 and its non-mammalian homologue, frequenin, are members of a highly conserved EF-hand Ca(2+) binding protein family, our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction.
Bahi
Nadia
N
Institut Cochin, INSERM Unité 567, CNRS UMR 8104, Université Paris V, CHU Cochin, 24 rue du Faubourg Saint Jacques, 75 014 Paris, France.
Friocourt
Gaelle
G
Carrié
Alain
A
Graham
Margaret E
ME
Weiss
Jamie L
JL
Chafey
Philippe
P
Fauchereau
Fabien
F
Burgoyne
Robert D
RD
Chelly
Jamel
J
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002522:Chlorocebus aethiops; D006224:Cricetinae; D005089:Exocytosis / Q000502:physiology*; D013006:Growth Hormone / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D053577:Interleukin-1 Receptor Accessory Protein; D038901:X-Linked Intellectual Disability / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D012441:Saccharomyces cerevisiae; D017386:Sequence Homology, Amino Acid; D020798:Two-Hybrid System Techniques
D002135:Calcium-Binding Proteins; C407643:IL1RAPL1 protein, human; D007375:Interleukin-1; D053577:Interleukin-1 Receptor Accessory Protein; D009419:Nerve Tissue Proteins; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; C101464:frequenin calcium sensor proteins; D013006:Growth Hormone; D002118:Calcium