CaMKII: some basics to remember

The theme of Thursday’s Volen Center for Complex Systems annual retreat will be Breakthroughs in understanding the role of CaMKII in synaptic function and memory and honors the pioneering work of John Lisman. To help bring non-experts up to speed, we asked Neuroscience Ph.D. students Stephen D. Alkins and Johanna G. Flyer-Adams from the Griffith lab at Brandeis for a quick primer on CaMKII.

What’s a protein kinase? 

Protein kinases are enzymes that act by adding phosphate groups to other proteins – a process called phosphorylation. Phosphorylation of a protein usually initiates a cascade of downstream effects such as changes in the protein’s 3D shape,  changes in its interactions with other proteins, changes in its activity and changes in its localization. In causing these types of changes, kinases facilitate some of the most essential cellular and molecular processes required for survival and proper functionality.

Aren’t there lots of protein kinases? What makes CaMKII special? 

Among the roughly 500+ genes in the human genome encoding protein kinases, a kinase known as calcium (Ca2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylates serine or threonine residues in a broad array of target proteins.  Though found in many different tissues (skeletal muscle, cardiac muscle, spleen, etc.), there is a lot of CaMKII in the brain– about 1% of total forebrain protein and 2% of total hippocampal protein (in rats). Previous research, including pivotal contributions from the Lisman Lab at Brandeis University working in mammalian brain, has identified CaMKII as a cellular and molecular correlate of learning and memory through its multiple roles governing normal neuronal structure, synaptic strength, plasticity, and homeostasis. The Griffith Lab has been instrumental in demonstrating that these roles of the kinase are conserved in invertebrates.

Why do we think CaMKII might play a role in memory?

a) Location!

As previously mentioned, CaMKII accounts for up to 2% of all proteins in memory-important brain regions like the hippocampus. It’s also highly abundant at neuronal synapses, where neurons communicate with each other.

b) Function!

Memory is thought to require a process called long term potentiation (LTP) where two neurons, in response to environmental changes, will change the strength of the synaptic connections by which they communicate with each other—these changes will last even after the environmental input has disappeared. We know that CaMKII is required for LTP. We also know that the increases in neuronal calcium levels that accompany neuronal activation and cause LTP also allow CaMKII to phosphorylate itself. This autophosphorylation of CaMKII changes its kinase activity so that CaMKII can stay active well past the window of neuronal activation, essentially ‘storing’ the memory of previous neuronal activity—much like LTP!

c) Structure!

Ultimately, the issue with ‘molecular memory’ is that all proteins degrade over time, causing one to ask how we can remember things for so long when the original proteins that stored that memory no longer exist. CaMKII is such an exciting candidate for molecular memory because it is mostly found as a dodecameric holoenzyme—this means that CaMKII likes to exist as a big assembly of twelve identical CaMKII subunits. However, each CaMKII subunit retains its kinase activity even when all twelve are assembled. What’s interesting is that the autophosphorylation and activation of one CaMKII subunit (which happens when neurons are activated and intracellular calcium levels rise) actually makes it easier for the other CaMKII subunits in the twelve-unit holoenzyme to become autophosphorylated and activated. This means that maybe when an activated subunit is old and get degraded, another new CaMKII subunit could take its place among the twelve-unit holoenzyme—and become activated just like the old subunit, allowing for the ‘molecular memory’ to last beyond when proteins degrade!

CaMKII phosphorylation and activationCaMKII in more detail…

Calcium binds to the small protein calmodulin and forms (Ca2+/CaM), which acts as a ‘second messenger’ that increases in concentration when neurons are activated. CaMKII relies on calcium/calmodulin (Ca2+/CaM) binding to activate an individual domain containing a regulatory segment.  In conditions of low calcium, elements within the CaMKII regulatory segment will have less affinity for (Ca2+/CaM) binding, keeping CaMKII in an autoinhibited state.  In conditions of high calcium, (Ca2+/CaM) binding initiates phosphorylation at three threonine residue sites, including Thr286 which prevents rebinding of the regulatory segment, thus keeping CaMKII constitutively active even when calcium levels fall.  In this activated state CaMKII can autophosphorylate inactivated intra-kinase domains, and will undergo subunit exchange with neighboring inactivated CaMKII holoenzymes. Furthermore, mutation of CaMKII residues or binding sites in target proteins, such as postsynaptic glutamate (AMPA) receptors, disrupts establishment of long-term potentiation (LTP) in neurons.  Together, CaMKII’s role as molecular switch that bidirectionally, and autonomously regulates activity in neurons has earned it the illustrious title of a “memory molecule.”

What amino-acid manipulations might I hear about?

a) T286A:

Changing a threonine in a phosphorylation site to an alanine prevents phosphorylation at that site. Blocking Thr286 phosphorylation with a T286A mutation prevents CaMKII generation of autonomous activity that disrupts neuronal activity and results in learning deficits.

b) T286D:

Changing a threonine to an aspartate puts a negative charge at the site, often making it act like it’s always phosphorylated. In the case of CaMKII, a T286D mutation renders the kinase constitutively active, which can interrupt normal LTP induction and normal memory storage and acquisition.

To learn more:

Titia de Lange to receive 47th Rosenstiel Award

Professor Titia de Lange

The 47th Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Research has been awarded to Professor Titia de Lange of Rockefeller University for her studies on the protection of chromosome ends (telomeres) from degradation and rearrangement. Professor de Lange will receive the award on April 12, 2018 at Brandeis University where de Lange will present a public lecture.

Dr. de Lange’s laboratory identified and characterized the roles of proteins that compose the shelterin complex, which binds specifically to the special telomeric DNA sequences and maintains the stability of these ends.  Dr. de Lange’s work has shown that the shelterin complex and the unusual telomere-loop structure of telomere DNA prevent these ends from being detected as broken chromosome ends and thus protect telomeres from being degraded and rearranged as are the ends at chromosome breaks.  De Lange’s work has further shown that disabling different components of shelterin triggers different cellular alarms designed to detect broken and degraded DNA ends and leads to lethal chromosome rearrangements such as the fusion of chromosomes.  In addition, her lab has gained critical insights into the mechanisms of cellular response to the presence of DNA damage and recently has defined processes that lead to massive chromosome rearrangements (chromothripsis) associated with many human cancers.

She is the Leon Hess Professor and director of the Anderson Center for Cancer Research at Rockefeller University, as well as an American Cancer Society Research Professor.  Her honors include: the Life Sciences Breakthrough Prize, the Rosalind E. Franklin Award from the National Cancer Institute, the Vilcek Prize in Biomedical Sciences, election as a foreign member of the US National Academy of Sciences and as Fellow of the American Academy of Arts and Sciences.

The Rosenstiel Award has had a distinguished record of identifying and honoring pioneering scientists who subsequently have been honored with the Lasker and Nobel Prizes.  Professor de Lange joins a long list of past awardees.

Stanley Deser’s Influence on the 2017 Nobel Prize for Physics

Written by Albion Lawrence

Deser, Arnowitt, & Miser

Bornholm 1959
From the left, Richard Arnowitt, Charles Misner and Stanley Deser

Today’s Physics Nobel Prize to Rai Weiss, Kip Thorne, and Barry Barish for the detection by the LIGO experiment of gravitational waves is a well-deserved recognition of a remarkable achievement through perseverance. However, it is the nature of prizes such as the Nobel that they obscure the important efforts and insights of many scientists across space and time that lead to the result in question.

Stanley DeserThe extraction of a gravitational wave signal from the output of the LIGO detector requires understanding in advance what signals can be produced; these are based on numerical simulations of astrophysical events which provide templates that a signal must match.

This is possible due to the seminal work of Brandeis emeritus faculty Stanley Deser, with his colleagues Richard Arnowitt and Charles Misner, who developed the mathematical framework known as the ADM formalism, to treat general relativity as a Hamiltonian system; with this, the evolution in time of the gravitational field can be computed from initial conditions.

In addition, Stanley was instrumental in the LIGO experiment being funded in the first place. The story is best told by him in his inimitable style (here quoted from an email, and lightly expurgated):

“Marcel Bardon, then [director] of NSF physics, made me an offer I’d better not refuse. I was nominated to some advisory committee in order to plead for LIGO in front of my betters, who would then go to Congress, if convinced. Those were dark days for waves, experimentally; we (ADM) of course knew the Lord was not evil, but 3 suns’ worth we did not expect!….It worked quite well, and was duly made a line item.”

Additional information:

Rosbash, Hall & Young Awarded Nobel Prize

Michael Rosbash, Nobel Laureate

Brandeis researchers Michael Rosbash, the Peter Gruber Endowed Chair in Neuroscience, and Professor Emeritus of Biology Jeffrey C. Hall have received this year’s Nobel Prize in Physiology or Medicine, together with Michael Young from The Rockefeller University,  for their pioneering work on the molecular mechanisms controlling circadian rhythm.

More about Michael

More about Jeff

More about Drosophila

 

Searches for Tenure-Track Faculty in the Sciences, 2017

Brandeis has six open searches for tenure-track faculty in the Division of Science this fall, with the intent to strengthen cross-disciplinary studies across the sciences. We are looking forward to a busy season of intriguing seminars from candidates this winter.

  1. Assistant Professor of Biochemistry. Biochemistry is looking for a creative scientist to establish an independent research program addressing fundamental questions of biological, biochemical, or biophysical mechanism, and who will maintain a strong interest in teaching Biochemistry.
  2. Assistant Professor of Chemistry. Chemistry seeks a creative individual at the assistant professor level for a tenure-track faculty position in physical (especially theoretical/computational) chemistry, materials chemistry, or chemical biology.
  3. Assistant Professor of Computer Science. Computer Science invites applications for a full-time, tenure-track assistant professor, beginning Fall 2018, in the broad area of Machine Learning and Data Science, including but not limited to deep learning, statistical learning, large scale and cloud-based systems for data science, biologically inspired learning systems, and applications of analytics to real-world problems.
  4. Assistant Professor in Soft Matter or Biological Physics. Physics invites applications for the position of tenure-track Assistant Professor beginning in the fall of 2018 in the interdisciplinary areas of biophysics, soft condensed matter physics and biologically inspired material science.
  5. Assistant Professor or Associate Professor in Psychology. Psychology invites applications for a tenure track appointment at the rank of Assistant or Associate Professor, with a specialization in Aging, to start August 2018. They seek an individual with an active human research program in any aspect of aging, including cognitive, social, clinical and health psychology.
  6. Tenure Track Assistant Professor in Applied MathematicsMathematics invites applications for a tenure-track position in applied mathematics at the rank of assistant professor beginning fall 2018. An ideal candidate will be expected to help to build an applied mathematics program within the department, and to interact with other science faculty at Brandeis. Candidates from all areas of applied mathematics will be considered.

Brandeis University is an equal opportunity employer, committed to building a culturally diverse intellectual community, and strongly encourages applications from women and minorities.  Diversity in its student body, staff and faculty is important to Brandeis’ primary mission of providing a quality education.  The search committees are therefore particularly interested in candidates who, through their creative endeavors, teaching and/or service experiences, will increase Brandeis’ reputation for academic excellence and better prepare its students for a pluralistic society.

Jordan Pollack Receives Lifetime Achievement Award

Jordan Pollack

The International Society for Artificial Life. has awarded a lifetime achievement award to Jordan Pollack, Professor of Computer Science and Chairman of Computer Science department, for his work on robotics, computer-simulated evolution and artificial life forms. Pollack, who has been a Brandeis faculty member for the past 23 years, is also the director of the Dynamical & Evolutionary Machine Organization (DEMO). DEMO is a research lab where Pollack and his students study recurrent neural networks, evolutionary computation, and dynamical systems.

Pollack received the lifetime award last week (September 4-8) at The European Conference on Artificial Life 2017 in Lyon, France. Nick Moran and Jordan Pollack’s paper “Effects of Cooperative and Competitive Coevolution on Complexity in a Linguistic Prediction Game” (MITCogNet) also received the best paper award at the conference.

In an interview with Brandeis Now, Professor Pollack discusses his career and research.

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