Mary B. Kennedy

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Mary B. Kennedy, Allen and Lenabelle Davis Professor of Biology, Caltech Mary Kennedy.jpg
Mary B. Kennedy, Allen and Lenabelle Davis Professor of Biology, Caltech

Mary Bernadette Kennedy (born 1947) is an American biochemist and neuroscientist. She is a member of the American Academy of Arts and Sciences, and is the Allen and Lenabelle Davis Professor of Biology at the California Institute of Technology, where she has been a member of the faculty since 1981. Her research focuses on the molecular mechanisms of synaptic plasticity, the process underlying formation of memory in the central nervous system. Her lab uses biochemical and molecular biological methods to study the protein machinery within a structure called the postsynaptic density. Kennedy has published over 100 papers with over 20,000 total citations. [1]

Contents

Biography

Kennedy in 1986 Mary B. Kennedy 1986.png
Kennedy in 1986

Kennedy was born on July 4, 1947, in Pontiac, in the US state of Michigan. Her family moved to South Bend, Indiana in 1953, where her father owned a shoe store, and her mother was a homemaker. She is the oldest of six siblings, with four sisters and a brother. [2] [ failed verification ]

Kennedy received a Bachelor of Science degree in chemistry in 1969 from St. Mary's College in South Bend. In 1975, she earned a Ph.D. in biochemistry from Johns Hopkins University in the laboratory of William Lennarz. She moved into the field of neuroscience during postdoctoral fellowships at Harvard Medical School with Edward Kravitz, and then at Yale University with Paul Greengard. In 1981, she moved to Caltech as an assistant professor and was promoted to professor in 1992. She was named Allen and Lenabelle Davis Professor of Biology in 2002. [3]

Major scientific contributions

Her laboratory purified and characterized the synaptic signaling protein Calcium/calmodulin-dependent protein kinase II (CaMKII) in 1983 [4] and showed that it is 1-2% of forebrain protein, [5] is a major constituent of the postsynaptic density, [6] and is regulated by autophosphorylation following activation by synaptic activity. [7]

Her lab later used micro-sequencing, molecular cloning, and immunocytochemistry to identify the central PSD scaffold protein PSD-95 and its three repeated domains later termed PDZ domains. [8] With Peter Seeburg, they then showed that the second PDZ domain binds a terminal S-X-V motif at the carboxyl tail of GluN2B, an NMDA receptor subunit. [9] PDZ domains are now known to be ubiquitous in scaffold proteins where they immobilize other proteins by binding to their C-terminal ligands. [10] Her work was the first discovery of a PDZ domain and established that the PSD is a scaffold containing signaling enzymes and receptors that function as a molecular machine to regulate synaptic strength. [11] [12]

Recent work concerns the role of the multifunctional PSD protein synGAP in regulating AMPA receptor insertion into the membrane [13] and trapping of AMPA receptors in the PSD. [14] She is collaborating with Tom Bartol and Terry Sejnowski at the Salk Institute to create kinetic models of biochemical signaling in postsynaptic spines. [15] [16]

Honors and awards

Related Research Articles

<span class="mw-page-title-main">AMPA receptor</span> Transmembrane protein family

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is an ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synaptic transmission in the central nervous system (CNS). It has been traditionally classified as a non-NMDA-type receptor, along with the kainate receptor. Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. The GRIA2-encoded AMPA receptor ligand binding core was the first glutamate receptor ion channel domain to be crystallized.

In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory.

<span class="mw-page-title-main">Postsynaptic density</span>

The postsynaptic density (PSD) is a protein dense specialization attached to the postsynaptic membrane. PSDs were originally identified by electron microscopy as an electron-dense region at the membrane of a postsynaptic neuron. The PSD is in close apposition to the presynaptic active zone and ensures that receptors are in close proximity to presynaptic neurotransmitter release sites. PSDs vary in size and composition among brain regions, and have been studied in great detail at glutamatergic synapses. Hundreds of proteins have been identified in the postsynaptic density, including glutamate receptors, scaffold proteins, and many signaling molecules.

<span class="mw-page-title-main">PDZ domain</span>

The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals. Proteins containing PDZ domains play a key role in anchoring receptor proteins in the membrane to cytoskeletal components. Proteins with these domains help hold together and organize signaling complexes at cellular membranes. These domains play a key role in the formation and function of signal transduction complexes. PDZ domains also play a highly significant role in the anchoring of cell surface receptors to the actin cytoskeleton via mediators like NHERF and ezrin.

Calmodulin-binding proteins are, as their name implies, proteins which bind calmodulin. Calmodulin can bind to a variety of proteins through a two-step binding mechanism, namely "conformational and mutually induced fit", where typically two domains of calmodulin wrap around an emerging helical calmodulin binding domain from the target protein.

Ca<sup>2+</sup>/calmodulin-dependent protein kinase II

Ca2+
/calmodulin-dependent protein kinase II is a serine/threonine-specific protein kinase that is regulated by the Ca2+
/calmodulin complex. CaMKII is involved in many signaling cascades and is thought to be an important mediator of learning and memory. CaMKII is also necessary for Ca2+
 homeostasis and reuptake in cardiomyocytes, chloride transport in epithelia, positive T-cell selection, and CD8 T-cell activation.

<span class="mw-page-title-main">DLG4</span> Mammalian protein found in Homo sapiens

PSD-95 also known as SAP-90 is a protein that in humans is encoded by the DLG4 gene.

<span class="mw-page-title-main">Calcium/calmodulin-dependent protein kinase type II subunit alpha</span> Protein-coding gene in the species Homo sapiens

Calcium/calmodulin-dependent protein kinase type II subunit alpha (CAMKIIα), a.k.a.Ca2+/calmodulin-dependent protein kinase II alpha, is one subunit of CamKII, a protein kinase (i.e., an enzyme which phosphorylates proteins) that in humans is encoded by the CAMK2A gene.

<span class="mw-page-title-main">DLG1</span> Protein-coding gene in the species Homo sapiens

Discs large homolog 1 (DLG1), also known as synapse-associated protein 97 or SAP97, is a scaffold protein that in humans is encoded by the SAP97 gene.

<span class="mw-page-title-main">CASK</span> Protein-coding gene in humans

Peripheral plasma membrane protein CASK is a protein that in humans is encoded by the CASK gene. This gene is also known by several other names: CMG 2, calcium/calmodulin-dependent serine protein kinase 3 and membrane-associated guanylate kinase 2. CASK gene mutations are the cause of XL-ID with or without nystagmus and MICPCH, an X-linked neurological disorder.

<span class="mw-page-title-main">DLG3</span> Protein-coding gene in humans

Disks large homolog 3 (DLG3) also known as neuroendocrine-DLG or synapse-associated protein 102 (SAP-102) is a protein that in humans is encoded by the DLG3 gene. DLG3 is a member of the membrane-associated guanylate kinase (MAGUK) superfamily of proteins.

<span class="mw-page-title-main">GRIN2B</span> Protein-coding gene in the species Homo sapiens

Glutamate [NMDA] receptor subunit epsilon-2, also known as N-methyl D-aspartate receptor subtype 2B, is a protein that in humans is encoded by the GRIN2B gene.

<span class="mw-page-title-main">GRIN2A</span> Protein-coding gene in the species Homo sapiens

Glutamate [NMDA] receptor subunit epsilon-1 is a protein that in humans is encoded by the GRIN2A gene. With 1464 amino acids, the canonical GluN2A subunit isoform is large. GluN2A-short isoforms specific to primates can be produced by alternative splicing and contain 1281 amino acids.

<span class="mw-page-title-main">SHANK2</span> Protein-coding gene in the species Homo sapiens

SH3 and multiple ankyrin repeat domains protein 2 is a protein that in humans is encoded by the SHANK2 gene. Two alternative splice variants, encoding distinct isoforms, are reported. Additional splice variants exist but their full-length nature has not been determined.

<span class="mw-page-title-main">GRIN2C</span> Protein-coding gene in the species Homo sapiens

Glutamate [NMDA] receptor subunit epsilon-3 is a protein that in humans is encoded by the GRIN2C gene.

<span class="mw-page-title-main">SYNGAP1</span> Protein in Homo sapiens

Synaptic Ras GTPase-activating protein 1, also known as synaptic Ras-GAP 1 or SYNGAP1, is a protein that in humans is encoded by the SYNGAP1 gene. SYNGAP1 is a ras GTPase-activating protein that is critical for the development of cognition and proper synapse function. Mutations in humans can cause intellectual disability, epilepsy, autism and sensory processing deficits.

<span class="mw-page-title-main">CACNG2</span> Protein-coding gene in the species Homo sapiens

Calcium channel, voltage-dependent, gamma subunit 2, also known as CACNG2 or stargazin is a protein that in humans is encoded by the CACNG2 gene.

<span class="mw-page-title-main">DLGAP1</span> Protein-coding gene in the species Homo sapiens

Disks large-associated protein 1 (DAP-1), also known as guanylate kinase-associated protein (GKAP), is a protein that in humans is encoded by the DLGAP1 gene. DAP-1 is known to be highly enriched in synaptosomal preparations of the brain, and present in the post-synaptic density.

<span class="mw-page-title-main">LRRC7</span> Protein-coding gene in the species Homo sapiens

Leucine rich repeat containing 7 also known as LRRC7, Densin-180, or LAP1 is a protein which in humans is encoded by the LRRC7 gene.

<span class="mw-page-title-main">Synaptic stabilization</span> Modifying synaptic strength via cell adhesion molecules

Synaptic stabilization is crucial in the developing and adult nervous systems and is considered a result of the late phase of long-term potentiation (LTP). The mechanism involves strengthening and maintaining active synapses through increased expression of cytoskeletal and extracellular matrix elements and postsynaptic scaffold proteins, while pruning less active ones. For example, cell adhesion molecules (CAMs) play a large role in synaptic maintenance and stabilization. Gerald Edelman discovered CAMs and studied their function during development, which showed CAMs are required for cell migration and the formation of the entire nervous system. In the adult nervous system, CAMs play an integral role in synaptic plasticity relating to learning and memory.

References

  1. ↑ "Mary B. Kennedy". Google Scholar.
  2. ↑ Kennedy, M.B. (2018). Personal Communication
  3. ↑ "Mary B. Kennedy". Caltech Division of Biology and Biological Engineering. Archived from the original on 2018-08-11. Retrieved 2017-10-12.
  4. ↑ Bennett, M.K.; Erondu, N.E.; Kennedy, M.B. (1983). "Purification and characterization of a calmodulin-dependent protein kinase that is highly concentrated in brain". J Biol Chem. 258 (20): 12735–12744. doi: 10.1016/S0021-9258(17)44239-6 . PMID   6313675.
  5. ↑ Erondu, N.E.; Kennedy, M.B. (1985). "Regional distribution of type II Ca2+/calmodulin-dependent protein kinase in rat brain". J Neurosci. 5 (12): 3270–3277. doi: 10.1523/JNEUROSCI.05-12-03270.1985 . PMC   6565219 . PMID   4078628.
  6. ↑ Kennedy, M.B.; Bennett, M.K.; Erondu, N.E. (1983). "Biochemical and immunochemical evidence that the "major postsynaptic density protein" is a subunit of a calmodulin-dependent protein kinase". Proc Natl Acad Sci USA. 80 (23): 7357–7361. Bibcode:1983PNAS...80.7357K. doi: 10.1073/pnas.80.23.7357 . PMC   390054 . PMID   6580651.
  7. ↑ Miller, S.G.; Kennedy, M.B. (1986). "Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch". Cell. 44 (6): 861–870. doi:10.1016/0092-8674(86)90008-5. PMID   3006921. S2CID   491812.
  8. ↑ Cho, K.-O.; Hunt, C.A.; Kennedy, M.B. (1992). "The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein". Neuron . 9 (5): 929–942. doi:10.1016/0896-6273(92)90245-9. PMID   1419001. S2CID   28528759.
  9. ↑ Kornau, H.-C.; Schenker, L.T.; Kennedy, M.B.; Seeburg, P.H. (1995). "Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95". Science. 269 (5231): 1737–1740. Bibcode:1995Sci...269.1737K. doi:10.1126/science.7569905. PMID   7569905. ProQuest   213563617.
  10. ↑ Kornau, H.-C.; Seeburg, P.H.; Kennedy, M.B. (1997). "Interaction of ion channels and receptors with PDZ domain proteins". Curr Opin Neurobiol. 7 (3): 368–373. doi:10.1016/S0959-4388(97)80064-5. PMID   9232802. S2CID   24653335.
  11. ↑ Kennedy, M.B. (1997). "The postsynaptic density at glutamatergic synapses". Trends Neurosci. 20 (6): 264–268. doi:10.1016/S0166-2236(96)01033-8. PMID   9185308. S2CID   41855275.
  12. ↑ Kennedy, M.B. (2000). "Signal-processing machines at the postsynaptic density". Science. 290 (5492): 750–754. Bibcode:2000Sci...290..750K. doi:10.1126/science.290.5492.750. PMID   11052931.
  13. ↑ Walkup, W.G.t.; Washburn, L.; Sweredoski, M.J.; Carlisle, H.J.; Graham, R.L.; Hess, S.; Kennedy, M.B. (2015). "Phosphorylation of synaptic GTPase-activating protein (synGAP) by Ca2+/calmodulin-dependent protein kinase II (CaMKII) and cyclin-dependent kinase 5 (CDK5) alters the ratio of its GAP activity toward ras and rap GTPases". J Biol Chem. 290 (8): 4908–4927. doi: 10.1074/jbc.M114.614420 . PMC   4335230 . PMID   25533468.
  14. ↑ Walkup, W.G.t.; Mastro, T.L.; Schenker, L.T.; Vielmetter, J.; Hu, R.; Iancu, A.; Reghunathan, M.; Bannon, B.D.; Kennedy, M.B. (2016). "A model for regulation by SynGAP-alpha1 of binding of synaptic proteins to PDZ-domain 'Slots' in the postsynaptic density". eLife. 5: e16813. doi: 10.7554/eLife.16813 . PMC   5040590 . PMID   27623146.
  15. ↑ Stefan, M.I.; Bartol, T.M.; Sejnowski, T.J.; Kennedy, M.B. (2014). "Multi-state modeling of biomolecules". PLOS Comput Biol . 10 (9): e1003844. Bibcode:2014PLSCB..10E3844S. doi: 10.1371/journal.pcbi.1003844 . PMC   4201162 . PMID   25254957.
  16. ↑ Bartol, T.M.; Keller, D.X.; Kinney, J.P.; Bajaj, C.L.; Harris, K.M.; Sejnowski, T.J.; Kennedy, M.B. (2015). "Computational reconstitution of spine calcium transients from individual proteins". Front Synaptic Neurosci . 07: 17. doi: 10.3389/fnsyn.2015.00017 . PMC   4595661 . PMID   26500546.
  17. ↑ Strobel, Gabrielle, "Research Funding in Neuroscience: A Profile of the McKnight Endowment Fund", 2010, pg. 137, Academic Press
  18. ↑ California Institute of Technology Annual Report 1991-92, page 6
  19. ↑ "Mary B. Kennedy". The Kennedy Lab.
  20. ↑ "Neurosciences". Fondation Ipsen. Archived from the original on 2017-07-21. Retrieved 2017-10-14.
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