Neurogranin Alters the Structure and Calcium Binding Properties of Calmodulin
Open accessAbstract
Neurogranin (Ng) is a member of the IQ motif class of calmodulin (CaM)-binding proteins, and interactions with CaM are its only known biological function. In this report we demonstrate that the binding affinity of Ng for CaM is weakened by Ca(2+) but to a lesser extent (2-3-fold) than that previously suggested from qualitative observations. We also show that Ng induced a >10-fold decrease in the affinity of Ca(2+) binding to the C-terminal domain of CaM with an associated increase in the Ca(2+) dissociation rate. We also discovered a modest, but potentially important, increase in the cooperativity in Ca(2+) binding to the C-lobe of CaM in the presence of Ng, thus sharpening the threshold for the C-domain to become Ca(2+)-saturated. Domain mapping using synthetic peptides indicated that the IQ motif of Ng is a poor mimetic of the intact protein and that the acidic sequence just N-terminal to the IQ motif plays an important role in reproducing Ng-mediated decreases in the Ca(2+) binding affinity of CaM. Using NMR, full-length Ng was shown to make contacts largely with residues in the C-domain of CaM, although contacts were also detected in residues in the N-terminal domain. Together, our results can be consolidated into a model where Ng contacts residues in the N- and C-lobes of both apo- and Ca(2+)-bound CaM and that although Ca(2+) binding weakens Ng interactions with CaM, the most dramatic biochemical effect is the impact of Ng on Ca(2+) binding to the C-terminal lobe of CaM.
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Common variants conferring risk of schizophrenia
†Genetic Risk and Outcome in Psychosis (GROUP), Stefansson, H., Ophoff, R. A., Steinberg, S., Andreassen, O. A., Cichon, S., Rujescu, D., Werge, T., Pietiläinen, O. P. H., Mors, O., et al. (2009) · Nature · doi:10.1038/nature08186 · Cited by 1,677 · see citing works
Calmodulin: a prototypical calcium sensor
Chin, D., & Means, A. R. (2000) · Trends in Cell Biology · doi:10.1016/s0962-8924(00)01800-6 · Cited by 1,531 · see citing works
Calcium-binding proteins in the nervous system
Baimbridge, K. G., Celio, M. R., & ROGERS, J. H. (1992) · Trends in Neurosciences · doi:10.1016/0166-2236(92)90081-i · Cited by 1,336 · see citing works
Structures and metal-ion-binding properties of the Ca2+-binding helix–loop–helix EF-hand motifs
Gifford, J. L., Walsh, M. P., & Vogel, H. J. (2007) · Biochemical Journal · doi:10.1042/bj20070255 · Cited by 899 · see citing works
Klee, C. B., & VANAMAN, T. C. (1982) · Advances in protein chemistry · doi:10.1016/s0065-3233(08)60470-2 · Cited by 778 · see citing works
Molecular and Structural Basis of Target Recognition by Calmodulin
Crivici, A., & Ikura, M. (1995) · Annual Review of Biophysics and Biomolecular Structure · doi:10.1146/annurev.bb.24.060195.000505 · Cited by 763 · see citing works
Yap, K. L., Kim, J., Truong, K., Sherman, M. S., Yuan, T., & Ikura, M. (2000) · Journal of Structural and Functional Genomics · doi:10.1023/a:1011320027914 · Cited by 550 · see citing works
Calcium binding to calmodulin and its globular domains
Linse, S. S., Helmersson, A., & Forsén, S. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)92938-8 · Cited by 484 · see citing works
Calmodulin signaling via the IQ motif
Bähler, M., & Rhoads, A. R. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)03239-2 · Cited by 475 · see citing works
Primary structure and transcriptional regulation of GAP-43, a protein associated with nerve growth
Basi, G. S., Jacobson, R. D., Virág, I., Schilling, J., & Skene, J. H. P. (1987) · Cell · doi:10.1016/0092-8674(87)90616-7 · Cited by 355 · see citing works
Regulation of calmodulin binding to P-57. A neurospecific calmodulin binding protein.
Alexander, K. A., Cimler, B. M., Meier, K. E., & Storm, D. R. (1987) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)45544-5 · Cited by 333 · see citing works
Structural diversity of calmodulin binding to its target sites
Tidow, H., & Nissen, P. (2013) · FEBS Journal · doi:10.1111/febs.12296 · Cited by 283 · see citing works
Baudier, J., Deloulme, J., DORSSELAER, A. V., Black, D. M., & Matthes, H. W. D. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)52425-x · Cited by 274 · see citing works
Purification of a novel calmodulin-binding protein from bovine cerebral cortex membranes
Andreasen, T. J., Luetje, C. W., Heideman, W., & Storm, D. R. (1983) · Biochemistry · doi:10.1021/bi00289a001 · Cited by 225 · see citing works
RC3/neurogranin, a postsynaptic calpacitin for setting the response threshold to calcium influxes
Gerendasy, D. D., & Sutcliffe, J. G. (1997) · Molecular Neurobiology · doi:10.1007/bf02740632 · Cited by 212 · see citing works
Kakiuchi, S., Yasuda, S., Yamazaki, R., Teshima, Y., Kanda, K., Kakiuchi, R., & Sobue, K. (1982) · The Journal of Biochemistry · doi:10.1093/oxfordjournals.jbchem.a134019 · Cited by 212 · see citing works
Calmodulin as a direct detector of Ca2+ signals
Faas, G. C., Raghavachari, S., Lisman, J. E., & Módy, I. (2011) · Nature Neuroscience · doi:10.1038/nn.2746 · Cited by 200 · see citing works
Subtractive cDNA cloning of RC3, a rodent cortex‐enriched mRNA encoding a novel 78 residue protein
Watson, J. B., Battenberg, E. L. F., Wong, K. K., et al. (1990) · Journal of Neuroscience Research · doi:10.1002/jnr.490260402 · Cited by 196 · see citing works
Identification of the protein kinase C phosphorylation site in neuromodulin
Apel, E. D., Byford, M. F., Au, D. C., et al. (1990) · Biochemistry · doi:10.1021/bi00461a017 · Cited by 165 · see citing works
Chapman, E. R., Au, D. C., Alexander, K. A., et al. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)52422-4 · Cited by 161 · see citing works
Peersen, O. B., Madsen, T. S., & Falke, J. J. (1997) · Protein Science · doi:10.1002/pro.5560060406 · Cited by 156 · see citing works
Malmendal, A., Evenäs, J., Forsén, S., & Akke, M. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.3188 · Cited by 152 · see citing works
Calcium binding to complexes of calmodulin and calmodulin binding proteins
Olwin, B. B., & Storm, D. R. (1985) · Biochemistry · doi:10.1021/bi00348a037 · Cited by 151 · see citing works
Evenäs, J., Forsén, S., Malmendal, A., et al. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.2770 · Cited by 127 · see citing works
Johnson, J. D., Snyder, C., Walsh, M., et al. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.2.761 · Cited by 125 · see citing works
Molecular mechanisms of calmodulin's functional versatility
Zhang, M., & Yuan, T. (1998) · Biochemistry and Cell Biology · doi:10.1139/o98-027 · Cited by 113 · see citing works
A New Role for IQ Motif Proteins in Regulating Calmodulin Function
Putkey, J. A., Kleerekoper, Q., Gaertner, T. R., & Waxham, M. N. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c300372200 · Cited by 110 · see citing works
Self-citationIsolation, sequence, and developmental profile of a brain-specific polypeptide, PEP-19.
Ziai, R., Pan, Y. C., Hulmes, J. D., et al. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.21.8420 · Cited by 105 · see citing works
Molecular mechanisms of calmodulin's functional versatility
Zhang, M., & Yuan, T. (1998) · Biochemistry and Cell Biology · doi:10.1139/bcb-76-2-3-313 · Cited by 102 · see citing works
Interactions between Domains of Apo Calmodulin Alter Calcium Binding and Stability
Sorensen, B. R., & Shea, M. A. (1998) · Biochemistry · doi:10.1021/bi9718200 · Cited by 98 · see citing works
Mutational and biophysical studies suggest RC3/neurogranin regulates calmodulin availability.
Gerendasy, D. D., Herron, S. R., Watson, J. B., & Sutcliffe, J. G. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31806-9 · Cited by 97 · see citing works
Gaertner, T. R., Putkey, J. A., & Waxham, M. N. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405352200 · Cited by 96 · see citing works
Self-citationA Peptide Model for Calmodulin Trapping by Calcium/Calmodulin-dependent Protein Kinase II
Putkey, J. A., & Waxham, M. N. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.47.29619 · Cited by 94 · see citing works
Self-citationCharacterization of a 7.5-kDa Protein Kinase C Substrate (RC3 Protein, Neurogranin) from Rat Brain
Huang, K., Huang, F. L., & Chen, H. C. (1993) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1993.1463 · Cited by 89 · see citing works
Gerendasy, D. D., Herron, S. R., Jennings, P. A., et al. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.12.6741 · Cited by 85 · see citing works
Evenäs, J., Malmendal, A., & Akke, M. (2001) · Structure · doi:10.1016/s0969-2126(01)00575-5 · Cited by 84 · see citing works
Yazawa, M., Ikura, M., Hikichi, K., et al. (1987) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)60909-3 · Cited by 82 · see citing works
Hoffman, L., Farley, M. M., & Waxham, M. N. (2013) · Biochemistry · doi:10.1021/bi3016586 · Cited by 76 · see citing works
Self-citationSangameswaran, L., Hempstead, J. L., & Morgan, J. P. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.14.5651 · Cited by 72 · see citing works
Kumar, V., Chichili, V. P. R., Zhong, L., Tang, X., Velázquez‐Campoy, A., Sheu, F., Seetharaman, J., Gerges, N. Z., & Sivaraman, J. (2013) · Scientific Reports · doi:10.1038/srep01392 · Cited by 68 · see citing works
Chang, J. W., SCHUMACHER, E., Coulter, P. M., et al. (1997) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199710000-00004 · Cited by 65 · see citing works
Broadbelt, K. G., Ramprasaud, A., & Jones, L. B. (2006) · Schizophrenia Research · doi:10.1016/j.schres.2006.04.028 · Cited by 64 · see citing works
A Serial Analysis of Gene Expression Profile of the Alzheimer’s Disease Tg2576 Mouse Model
George, A. J., Gordon, L., Beißbarth, T., Koukoulas, I., Holsinger, R. M. D., Perreau, V. M., Cappai, R., Tan, S., Masters, C. L., Scott, H. S., et al. (2009) · Neurotoxicity Research · doi:10.1007/s12640-009-9112-3 · Cited by 62 · see citing works
Sorensen, B. R., Faga, L. A., Hultman, R. C., et al. (2001) · Biochemistry · doi:10.1021/bi011718+ · Cited by 60 · see citing works
Coldren, C. D., Lai, Z. C., Shragg, P., Rossi, E. G., Glidewell, S. C., Zuffardi, O., Mattina, T., Ivy, D. D., Curfs, L., Mattson, S. N., et al. (2008) · Neurogenetics · doi:10.1007/s10048-008-0157-x · Cited by 60 · see citing works
Neurogranin is locally concentrated in rat cortical and hippocampal neurons
Neuner‐Jehle, M., Denizot, J., & Mallet, J. J. (1996) · Brain Research · doi:10.1016/0006-8993(96)00786-x · Cited by 52 · see citing works
Association of the gene encoding neurogranin with schizophrenia in males
Ruano, D., Aulchenko, Y. S., Macedo, A., Soares, M. J., Valente, J., Azevedo, M. H., Hutz, M. H., Gama, C. S., Lobato, M. I. R., Belmonte-de-Abreu, P. S., et al. (2006) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2006.10.008 · Cited by 52 · see citing works
Theoharis, N. T., Sorensen, B. R., Theisen-Toupal, J. C., et al. (2007) · Biochemistry · doi:10.1021/bi7013129 · Cited by 51 · see citing works
Neurogranin Targets Calmodulin and Lowers the Threshold for the Induction of Long-Term Potentiation
Zhong, L., & Gerges, N. Z. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041275 · Cited by 49 · see citing works
PEP-19, an Intrinsically Disordered Regulator of Calmodulin Signaling
Kleerekoper, Q., & Putkey, J. A. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m808067200 · Cited by 47 · see citing works
Self-citationAcidic/IQ Motif Regulator of Calmodulin
Putkey, J. A., Waxham, M. N., Gaertner, T. R., Savannah, K. J. B., Goldsmith, M. R., Kubota, Y., & Kleerekoper, Q. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m703831200 · Cited by 41 · see citing works
Self-citationWu, J., Huang, K., & Huang, F. L. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01963.x · Cited by 39 · see citing works
Calmodulin content in specific brain areas
Biber, A., Schmid, G., & Hempel, K. (1984) · Experimental Brain Research · doi:10.1007/bf00236287 · Cited by 34 · see citing works
Pohlack, S. T., Nees, F., Ruttorf, M., Witt, S. H., Nieratschker, V., Rietschel, M., & Flor, H. (2011) · Molecular Psychiatry · doi:10.1038/mp.2011.66 · Cited by 33 · see citing works
Neurogranin binds to phosphatidic acid and associates to cellular membranes
Domínguez-González, I., Vázquez‐Cuesta, S., Algaba, A., & Díez-Guerra, F. J. (2007) · Biochemical Journal · doi:10.1042/bj20061483 · Cited by 33 · see citing works
Cui, Y., Wen, J., Sze, K. H., et al. (2003) · Analytical Biochemistry · doi:10.1016/s0003-2697(03)00007-1 · Cited by 32 · see citing works
Kubota, Y., Putkey, J. A., Shouval, H. Z., & Waxham, M. N. (2007) · Journal of Neurophysiology · doi:10.1152/jn.00876.2007 · Cited by 29 · see citing works
Self-citationIntra- and Interdomain Effects Due to Mutation of Calcium-binding Sites in Calmodulin
Xiong, L., Kleerekoper, Q., Wang, X., & Putkey, J. A. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.065243 · Cited by 24 · see citing works
Self-citationLobe Specific Ca2+-Calmodulin Nano-Domain in Neuronal Spines: A Single Molecule Level Analysis
Kubota, Y., & Waxham, M. N. (2010) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1000987 · Cited by 23 · see citing works
Self-citationStructural Characterization of the Interaction of Human Lactoferrin with Calmodulin
Gifford, J., Ishida, H., & Vogel, H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0051026 · Cited by 22 · see citing works
Intrinsically Disordered PEP-19 Confers Unique Dynamic Properties to Apo and Calcium Calmodulin
Wang, X., Kleerekoper, Q., Xiong, L.-W., & Putkey, J. A. (2010) · Biochemistry · doi:10.1021/bi100500m · Cited by 16 · see citing works
Self-citationGenetic and functional analysis of the gene encoding neurogranin in schizophrenia
Shen, Y., Tsai, H.-M., Cheng, M.-C., Hsu, S.-H., Chen, S., & Chen, C. (2012) · Schizophrenia Research · doi:10.1016/j.schres.2012.01.011 · Cited by 16 · see citing works
Ehrhardt, M. R., Erijman, L., Weber, G., et al. (1996) · Biochemistry · doi:10.1021/bi951267r · Cited by 15 · see citing works
The Calmodulin Regulator Protein, PEP-19, Sensitizes ATP-induced Ca2+ Release
Wang, X., Xiong, L.-W., Ayadi, A. E., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.411314 · Cited by 14 · see citing works
Self-citationStructure and regulation of the gene encoding the neuron-specific protein PEP-19
Sangameswaran, L., & Morgan, J. I. (1993) · Molecular Brain Research · doi:10.1016/0169-328x(93)90149-j · Cited by 11 · see citing works
Mattson, M. (1999) · doi:10.1002/(sici)1097-4547(19991001)58:1
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- Authors
- Hoffman, L., Chandrasekar, A., Wang, X., Putkey, J. A., & Waxham, M. N.
- Corresponding author
- Waxham, M. Neal
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 289
- Issue
- 21
- Pages
- 14644-14655
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4031520
- OpenAlex
- W2054856526
- Cited by
- 66
- References
- 66
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 5 · 2023: 2 · 2022: 4 · 2021: 8 · 2020: 8 · 2019: 7 · 2018: 4 · 2017: 7 · 2016: 3 · 2015: 2 · 2014: 3
- FWCI
- 2.05
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (GM097553, GM104290)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- neurogranin, calmodulin, IQ motif, calcium binding, protein-protein interaction, calcium cooperativity, domain mapping, calmodulin-binding proteins
- MeSH terms
- Amino Acid Sequence, Binding Sites, Binding, Competitive, Calcium, Calmodulin, Calorimetry, Humans, Kinetics, Molecular Sequence Data, Magnetic Resonance Spectroscopy, Protein Binding, Blotting, Western, Amino Acid Motifs, Neurogranin
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