The C-Terminal Tail of Human Neuronal Calcium Sensor 1 Regulates the Conformational Stability of the Ca²⁺-Activated State

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• 作者：Pé ; tur O. Heidarsson¹ ; Ida J. Bjerrum-Bohr¹ ; ¹ ; Gitte A. Jensen¹ ; Olaf Pongs² ; Bryan E. Finn³ ; Flemming M. Poulsen¹ ; ^&dagger ; ; Birthe B. Kragelund¹ ; ^{bbk@bio.ku.dk}
• 关键词：NCS-1 ; neuronal calcium sensor 1 ; 3D ; three-dimensional ; HC ; hydrophobic crevice ; NOESY ; nuclear Overhauser enhancement spectroscopy ; HSQC ; heteronuclear single-quantum coherence ; TOCSY ; total correlated spectroscopy ; NOE ; nuclear Overhauser enhancement
• 刊名：Journal of Molecular Biology
• 出版年：2012
• 期刊代码：102_00222836
• 类别：imm
• 出版时间：16 March, 2012
• 卷：417
• 期：1-2
• 页码：51-64
• 文件大小：1336 K

摘要

Neuronal calcium sensor 1 (NCS-1) and orthologs are expressed in all organisms from yeast to humans. In the latter, NCS-1 plays an important role in neurotransmitter release and interacts with a plethora of binding partners mostly through a large solvent-exposed hydrophobic crevice. The structural basis behind the multispecific binding profile is not understood. To begin to address this, we applied NMR spectroscopy to determine the solution structure of calcium-bound human NCS-1. The structure in solution demonstrates interdomain flexibility and, in the absence of a binding partner, the C-terminal tail residues occupy the hydrophobic crevice as a ligand mimic. A variant with a C-terminal tail deletion shows lack of a defined structure but maintained cooperative unfolding and dramatically reduced global stability. The results suggest that the C-terminal tail is important for regulating the conformational stability of the Ca²⁺-activated state. Furthermore, a single amino acid mutation that was recently diagnosed in a patient with autistic spectrum disorder was seen to affect the C-terminal tail and binding crevice in NCS-1.