Prof. Jim Ames and graduate student Congmin Li, in collaboration with researchers from University of Cambridge and University of Toronto, have solved the structure of a protein complex that is implicated in Alzheimer’s disease. This work is published in the Proceedings of the National Academy of Science. Dynamic increases in cytosolic free Ca2+ concentration regulate many cellular events, including acute and long-term changes in neuronal activity. Release of Ca2+from intracellular stores is controlled by intracellular Ca2+channels, the most common of which are inositol 1,4,5-trisphosphate receptors (InsP3Rs). Dual regulation of InsP3Rs by InsP3and Ca2+facilitates regenerative Ca2+release, generating Ca2+signals of remarkable versatility and spatio-temporal complexity.Calcium-binding protein 1 (CaBP1) is a neuron-specific member of the calmodulin superfamily that regulates InsP3Rs. Mutations in CaBP1 and InsP3R that disrupt Ca2+-dependent channel regulation are genetically linked to neuronal degenerative diseases including Alzheimer’s Disease. CaBP1 inhibits InsP3-evoked Ca2+release by slowing the rate of InsP3R channel opening. CaBP1 binds via its C-lobe to the cytosolic N-terminal region (NT, residues 1-604) of InsP3R1. The Ames Laboratory combines NMR, mutagenesis, cross-linking, and functional analyses to define, at the atomic level, the structural interactions between CaBP1 and InsP3Rs. NMR paramagnetic relaxation enhancement (PRE) analysis demonstrates that a cluster of hydrophobic residues (V101, L104 and V162) within the C-lobe of CaBP1 interact with a complementary cluster of hydrophobic residues (L302, I364 and L393) in the β-domain of the InsP3-binding core (IBC) (Fig. 1). Our structural analysis reveals that CaBP1 forms an extended tetrameric turret attached by the tetrameric NT to the cytosolic vestibule of the InsP3R pore. InsP3activates InsP3Rs by initiating conformational changes that lead to disruption of an inter-subunit interaction between a 'hot-spot' loop in the suppressor domain (SD, pink) and the IBC β-domain (yellow). Targeted cross-linking of residues that contribute to this interface show that InsP3attenuates cross-linking, while CaBP1 promotes it. We conclude that CaBP1 inhibits InsP3R activity by restricting the inter-subunit movements that initiate gating. This work is supported by the National Institutes of Health. Click here to access the article in PNAS.
-UC Davis Department of Chemistry, Featured Stories December, 2014
Protein Structures Give Disease Clues:
"Using some of the most powerful nuclear magnetic resonance equipment available, researchers at the University of California, Davis, are making discoveries about the shape and structure of biological molecules — potentially leading to new ways to treat or prevent diseases such as breast cancer and Alzheimer’s disease."
-UC Davis News and Information.
Read the article at http://news.ucdavis.edu/search/news_detail.lasso?id=10138