title: Structural and functional deficits in a neuronal calcium sensor-1 mutant identified in a case of autistic spectrum disorder.
abstract: 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.
authors.affiliation: The Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Mark T W
authors.initials: MT
authors.lastname: Handley
authors.forename: Lu-Yun
authors.initials: LY
authors.lastname: Lian
authors.forename: Lee P
authors.initials: LP
authors.lastname: Haynes
authors.forename: Robert D
authors.initials: RD
authors.lastname: Burgoyne
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D002118:Calcium / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053577:Interleukin-1 Receptor Accessory Protein / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D051580:Neuronal Calcium-Sensor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D013329:Structure-Activity Relationship; D021601:trans-Golgi Network / Q000187:drug effects / Q000378:metabolism
chemical_list: D053577:Interleukin-1 Receptor Accessory Protein; D050505:Mutant Proteins; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; C101464:frequenin calcium sensor proteins; D002118:Calcium