Three-dimensional Reconstructions of Calcium/Calmodulin-dependent (CaM) Kinase IIα and Truncated CaM Kinase IIα Reveal a Unique Organization for Its Structural Core and Functional Domains*

Studies of the structural organization of calcium/ calmodulin-dependent protein kinase IIα (CaM KIIα) and truncated CaM KIIα by three-dimensional electron microscopy and protein engineering show that the structures consist of 12 subunits that are organized in two stacked hexameric rings with 622 symmetry. The body of CaM KIIα is gear-shaped, consisting of six slanted flanges, and has six foot-like processes attached by narrow appendages to both ends of the flanges. Truncated CaM KIIα that lacks functional domains has a structure that is very similar to the body of CaM KIIα. Thus, the functional domains reside in the foot-like processes, and the association domain comprises the gear-shaped core. The ribbon diagram of the bilobate structure of CaM KI fits nicely in the envelope of the foot-like component and indicates that the crevice between the two lobes comprising the functional domains is near the middle portion of the foot. The clustering of the functional domains provides a favorable arrangement for the autophosphorylation reaction, and the unusual arrangement of the catalytic domain on extended tethers appears to be significant for the remarkable functional diversity of CaM KIIα in cellular regulation.

[1]  M K Bennett,et al.  Biochemical and immunochemical evidence that the "major postsynaptic density protein" is a subunit of a calmodulin-dependent protein kinase. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[2]  M. T. Davison,et al.  The calmodulin-dependent glycogen synthase kinase from rabbit skeletal muscle. Purification, subunit structure and substrate specificity. , 1983, European journal of biochemistry.

[3]  P. Greengard,et al.  Evidence that the major postsynaptic density protein is a component of a Ca2+/calmodulin-dependent protein kinase. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[4]  P. Greengard,et al.  Ca2+/calmodulin-dependent protein kinase II. Isozymic forms from rat forebrain and cerebellum. , 1985, The Journal of biological chemistry.

[5]  P. Kelly,et al.  Changes in the subcellular distribution of calmodulin-kinase II during brain development. , 1985, Brain research.

[6]  M. Kennedy,et al.  Distinct forebrain and cerebellar isozymes of type II Ca2+/calmodulin-dependent protein kinase associate differently with the postsynaptic density fraction. , 1985, The Journal of biological chemistry.

[7]  M. Kennedy,et al.  Regulation of brain Type II Ca 2+ calmodulin -dependent protein kinase by autophosphorylation: A Ca2+-triggered molecular switch , 1986, Cell.

[8]  M. Unser,et al.  A new resolution criterion based on spectral signal-to-noise ratios. , 1987, Ultramicroscopy.

[9]  Stephen G. Miller,et al.  Sequences of autophosphorylation sites in neuronal type II CaM kinase that control Ca2+-independent activity , 1988, Neuron.

[10]  M. Radermacher,et al.  Three-dimensional reconstruction of single particles from random and nonrandom tilt series. , 1988, Journal of electron microscopy technique.

[11]  M. Kennedy,et al.  Conserved and variable regions in the subunits of brain type II Ca2+/calmodulin-dependent protein kinase , 1988, Neuron.

[12]  P. Greengard,et al.  Ca2+/calmodulin-dependent protein kinase II: identification of threonine-286 as the autophosphorylation site in the alpha subunit associated with the generation of Ca2+-independent activity. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Lisman,et al.  A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[14]  M. Waxham,et al.  In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[15]  T Yamauchi,et al.  Structural features of Ca2+/calmodulin-dependent protein kinase II revealed by electron microscopy , 1991, The Journal of cell biology.

[16]  H. Schulman,et al.  Neuronal Ca2+/calmodulin-dependent protein kinases. , 1992, Annual review of biochemistry.

[17]  Alcino J. Silva,et al.  Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. , 1992, Science.

[18]  H. Schulman,et al.  Calmodulin Trapping by Calcium-Calmodulin-Dependent Protein Kinase , 1992, Science.

[19]  Maryann E Martone,et al.  Programs for visualization in three-dimensional microscopy , 1992, NeuroImage.

[20]  Alcino J. Silva,et al.  Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. , 1992, Science.

[21]  T. Baker,et al.  Three-dimensional structure of the truncated core of the Saccharomyces cerevisiae pyruvate dehydrogenase complex determined from negative stain and cryoelectron microscopy images. , 1992, The Journal of biological chemistry.

[22]  F A Quiocho,et al.  Modulation of calmodulin plasticity in molecular recognition on the basis of x-ray structures. , 1993, Science.

[23]  J. Frank,et al.  The ribosome at improved resolution: new techniques for merging and orientation refinement in 3D cryo-electron microscopy of biological particles. , 1994, Ultramicroscopy.

[24]  Lubert Stryer,et al.  Dual role of calmodulin in autophosphorylation of multifunctional cam kinase may underlie decoding of calcium signals , 1994, Neuron.

[25]  J. Lisman.  The CaM kinase II hypothesis for the storage of synaptic memory , 1994, Trends in Neurosciences.

[26]  H. Schulman,et al.  The multifunctional calcium/calmodulin-dependent protein kinase: from form to function. , 1995, Annual review of physiology.

[27]  S. Tonegawa,et al.  Limbic epilepsy in transgenic mice carrying a Ca2+/calmodulin-dependent kinase II alpha-subunit mutation. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[28]  R. Nicoll,et al.  Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[29]  W. Chiu,et al.  Assembly of VP26 in herpes simplex virus-1 inferred from structures of wild-type and recombinant capsids , 1995, Nature Structural Biology.

[30]  P. Penczek,et al.  Structure-Function Relationships of the Saccharomyces cerevisiae Fatty Acid Synthase , 1996, The Journal of Biological Chemistry.

[31]  M. Waxham,et al.  A Peptide Model for Calmodulin Trapping by Calcium/Calmodulin-dependent Protein Kinase II* , 1996, The Journal of Biological Chemistry.

[32]  A. Nairn,et al.  Structural Basis for the Autoinhibition of Calcium/Calmodulin-Dependent Protein Kinase I , 1996, Cell.

[33]  A Leith,et al.  SPIDER and WEB: processing and visualization of images in 3D electron microscopy and related fields. , 1996, Journal of structural biology.

[34]  J P Schroeter,et al.  SUPRIM: easily modified image processing software. , 1996, Journal of structural biology.

[35]  P. Penczek,et al.  Utility of Butvar support film and methylamine tungstate stain in three-dimensional electron microscopy: agreement between stain and frozen-hydrated reconstructions. , 1997, Journal of structural biology.

[36]  T. Soderling,et al.  Regulatory phosphorylation of AMPA-type glutamate receptors by CaM-KII during long-term potentiation. , 1997, Science.

[37]  Alcino J. Silva,et al.  Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. , 1998, Science.

[38]  D. Strickland,et al.  Three-Dimensional Structure of the Human Plasmin α2-Macroglobulin Complex , 1998 .

[39]  M. Neal Waxham,et al.  Identification of Domains Essential for the Assembly of Calcium/Calmodulin-dependent Protein Kinase II Holoenzymes* , 1998, The Journal of Biological Chemistry.

[40]  P. Gettins,et al.  On the structural changes of native human alpha2-macroglobulin upon proteinase entrapment. Three-dimensional structure of the half-transformed molecule. , 1998, The Journal of biological chemistry.

[41]  H. Schulman,et al.  Substrate-directed Function of Calmodulin in Autophosphorylation of Ca2+/Calmodulin-dependent Protein Kinase II* , 1998, The Journal of Biological Chemistry.

[42]  P. De Koninck,et al.  Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. , 1998, Science.

[43]  D. Strickland,et al.  Structural Details of Proteinase Entrapment by Human α2-Macroglobulin Emerge from Three-dimensional Reconstructions of Fab labeled Native, Half-transformed, and Transformed Molecules* , 1999, The Journal of Biological Chemistry.

[44]  H. Schulman,et al.  Functional Implications of the Subunit Composition of Neuronal CaM Kinase II* , 1999, The Journal of Biological Chemistry.

[45]  K. Shen,et al.  Dynamic control of CaMKII translocation and localization in hippocampal neurons by NMDA receptor stimulation. , 1999, Science.

[46]  R. Nicoll,et al.  Long-term potentiation--a decade of progress? , 1999, Science.