Structural and functional deficits in a neuronal calcium sensor-1 mutant identified in a case of autistic spectrum disorder.

Structural and functional deficits in a neuronal calcium sensor-1 mutant identified in a case of autistic spectrum disorder.

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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 Neuw Rebel Skinny Eternal Black Jeans 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 here 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.