Structural and Functional Deficits in a Neuronal Calcium Sensor-1 Mutant Identified in a Case of Autistic Spectrum Disorder

The Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Liverpool, United Kingdom.
PLoS ONE (Impact Factor: 3.23). 05/2010; 5(5):e10534. DOI: 10.1371/journal.pone.0010534
Source: PubMed


Neuronal calcium sensor-1 (NCS-1) is a Ca(2+) sensor protein that has been implicated in the regulation of various aspects of neuronal development and neurotransmission. It exerts its effects through interactions with a range of target proteins one of which is interleukin receptor accessory protein like-1 (IL1RAPL1) protein. Mutations in IL1RAPL1 have recently been associated with autism spectrum disorders and a missense mutation (R102Q) on NCS-1 has been found in one individual with autism. We have examined the effect of this mutation on the structure and function of NCS-1. From use of NMR spectroscopy, it appeared that the R102Q affected the structure of the protein particularly with an increase in the extent of conformational exchange in the C-terminus of the protein. Despite this change NCS-1(R102Q) did not show changes in its affinity for Ca(2+) or binding to IL1RAPL1 and its intracellular localisation was unaffected. Assessment of NCS-1 dynamics indicated that it could rapidly cycle between cytosolic and membrane pools and that the cycling onto the plasma membrane was specifically changed in NCS-1(R102Q) with the loss of a Ca(2+) -dependent component. From these data we speculate that impairment of the normal cycling of NCS-1 by the R102Q mutation could have subtle effects on neuronal signalling and physiology in the developing and adult brain.

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    • "In humans , the interaction is conserved , suggesting a potential role in pathology . IL1RAPL1 and NCS - 1 are implicated in X - linked mental retardation and autism ( Handley et al . , 2010 ; Pavlowsky et al . , 2010 ) . The autism - related missense ( R102Q ) mutation in NCS - 1 abolishes Ca 2+ dependence , owing to a weakened conformational stability of its C - terminus that affects the cytosolic - to - membrane cycling of NCS - 1 ( Heidarsson et al . , 2012 ) . Because Frq2 – NCS - 1 is a negative regulator of Ric8 , it "
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    • "NCS-1, the primordial member of the NCS family, has orthologues from Saccharomyces cerevisiae (Frq1) [11] to man and has been implicated in several neuronal functions including regulation of neurotransmitter release [12,13], membrane traffic [14], voltage gated Ca2+ channels [15-17], neuronal development [18,19], synaptic plasticity [20,21] and learning [22,23]. NCS-1 is N-terminally myristoylated which allows its association with the plasma membrane and the trans-Golgi network [7] and it cycles between membrane and cytosolic pools [24]. NCS-1 is known to interact with a wide range of potential target proteins [25,26] including phosphatidylinositol-4-kinase (PI4K) IIIβ [14,27] and its orthologue Pik1 in yeast [11], ARF1 [14,28], interleukin receptor accessory protein like-1 (IL1RAPL1) [29], TRPC5 channels [18], InsP(3) receptors [30] and dopamine D2 and D3 receptors [31]. "
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