Bacterial Chemotaxis and Human Memory: Pete and Repeat

Many do not place ‘bacteria’ and ‘memory’ in the same sentence. Normal human perception does not connect the two concepts. However, Mother Nature seems to have a more profound perception. The past 50 years or so of scientific investigation has shown how our uniqueness as humans is actually commonplace across all forms of life on Earth. Case in point, how closely associated molecular memory is between bacteria and human.

Bacteria use adaptation to signals as memory

Swimming bacteria do not move randomly in their environment. This behavior would be futile and counterproductive. Instead, bacteria are constantly monitoring their environment in search of food and poisons. Moving towards the former and away from the latter. This observation was first published in the late 19th century. Bacteria, like the famous and infamous E. coli, use molecular antennae to receive these important ‘signals’ as the basis in the decision of which direction to swim. What if the bacteria find a great place to reside with lots of food but still need to receive signals to ensure they remain there? The antennae have sections that can be modified easily and reversibly. These modifications, in the form of methylation, alter the sensitivity of the antenna protein to subsequent signals. Methylation allows these antennae not to receive the number of absolute signals but relative signals. In other words, the antenna protein through fine-tuned methylation detects changes in the number of signals now versus some time in the past. This is the basis of molecular memory.

These antennae are proteins called methyl-accepting chemotaxis proteins, or MCPs. MCPs accept methyl groups from the essential cofactor S-adenosylmethionine (aka SAM or AdoMet). AdoMet is essential to both prokaryotes and eukaryotes like humans. The methyl groups are added by a protein called CheR (pronounced ‘key R’) which transfers the methyl from AdoMet to very specific amino acid side groups of glutamate. The process, called O-methylation adds the methyl group to the single-bonded oxygen on the carboxyl.

O-methylation reaction
O-methylation reaction. Courtesy of www.brenda-enzymes.org.

The length of a bacterium’s molecular memory is very short in comparison to how we perceive memory at only a few seconds. But, to bacteria it is long enough to successfully navigate the environment with similar precision when concentrations of food or poison vary (up to several orders of magnitude, or ~1000x).

Does the basis of molecular memory in humans mimic bacteria?

Eukaryotes, including humans, use a very similar mechanism in signal transduction to bacteria. Phosphorylation (transferring a phosphate group from ATP or GTP to a protein amino acid) is the basis of all signal transduction and cell regulation. Bacteria use histidine kinases and response regulators, as do plants to some degree. However, the majority of regulation through signal transduction in eukaryotes is through two types of proteins, RAS proteins and the heterotrimeric G-proteins. G-proteins interact with membrane receptors that regulate their activity. What determines which surface receptors G-proteins interact with? Isoprenylcysteine methyltransferase, or ICMT, is one of two methyltransferases that regulate signal transduction activity. ICMT is a membrane protein that uses AdoMet to add methyl groups to isoprenylcysteine, a post-translationally modified cysteine residue on both heterotrimeric and RAS-related G proteins. Methylation regulates which receptors the G-proteins interact with, thus playing a major role in connecting the initial signal to downstream regulatory pathways. The carboxyl methylation essentially modulates G-protein signalling globally.

G-protein carboxyl methylation is regulated by GPCR signaling and, as seen above, GPCR signaling is regulated by G-protein carboxyl methylation. This feedback/feed forward loop could be seen as a form of molecular memory stored in methylation patterns. Within the brain, ICMT activity is almost exclusively found in the region controlling coordination of movement. Thus, methylation could be used to modulate certain neuronal signaling pathways which result in learned patterns of sensory-motor skills.

The only other major methyltransferase is from a protein known as PPMT. PPMT interacts with a major enzyme in signal termination, the protein phosphatase PP2A. PPMT adds methyl groups to the backbone carboxyl of a specific leucine in PP2A. This carboxyl methylation helps determine which B subunit PP2A interacts with and where in the cell PP2A can be found. PPMT structurally resembles CheR in bacterial memory. Moreover, the enzyme that removes the methyl group from PP2A, PME, structurally resembles the bacterial enzyme that removes methyls from MCPs, CheB.

PP2A is one of the major regulators of pathway coordination to maintain synaptic plasticity in the brain. Interestingly, methylation defects and PP2A-PME complexes are suggested to play a role in the cause of Alzheimer’s Disease and memory loss. Methylation defects leading to defective phosphatase activity of PP2A leads to accumulation of a phosphorylated subunit of the structural protein microtubule. In this phosphorylated form, the filaments used to keep axons structurally sound collapse and lead to loss of normal synapses. Therefore, molecular memory in the form of methylation plays a vital role in promoting normal brain activity and its disruption can ultimately lead to dementia. 

Chicken, meet egg. Egg, meet chicken.

So, from bacteria to human, carboxyl methylation is necessary for memory. Did these pathways evolve individually in parallel, or did the memory we have today originate in the predominant lifeforms found within us?

 

Suggested Reading

Li and Stock. (2009) Biol. Chem. 390: 1067-1096. DOI 10.1515/BC.2009.133

How do bacteria make decisions? Part 6: It takes a village

The marvels of single celled organisms is that they are able to integrate all kinds of stimuli and make one grand decision that affects how they proceed. Bacteria do in one cell what we as humans do with billions. However, do bacteria contain the ability to think as a group or community?

The answer is absolutely. It is called quorum sensing. The pioneer for this research is Bonnie Bassler from Princeton University. Listening to her tell her story of the curiosity she felt when observing how and why a certain group of bacteria emitted light, or bio-luminescence is great. (Watch here). Through her investigation with a insignificant bacterium, Vibrio harveyi, she opened up a whole new field of microbiology.

Many bacteria synthesize signaling molecules that serve as messages to other bacteria saying, “I am here”. Since bacteria don’t have senses that we are familiar with like sight and hearing, these signaling molecules tell other bacteria who is around. When there aren’t a lot of bacteria sending out the signal, no big decisions are made. However, when enough bacteria are around to tell all other village members the approximate population, all village members act together to make a committed decision. In the case of V. harveyi it is the production of a light emitting molecule, but for other bacterial species it may be activation of pathogenicity. From the perspective of the bacterium, you don’t want to decide alone to make a big commitment like invading another organism. By taking a bacterial census through quorum sensing, these bacteria make a educated decision only when their population is high enough to make an impact. For some species, this critical number may be less than ten. However, in some cases, the population needs to be in the millions.

I think bacteria can teach us a very important lesson via quorum sensing: don’t go it alone. It takes a village.

Azospirillum brasilense electron micrograph

Hooray for Failure! It’s Science’s way of telling you you’re not being creative enough

English: A diagram of a typical prokaryotic ce...
English: A diagram of a typical prokaryotic cell. This diagram, made in Adobe Illustrator, is an improved version of a similar diagram, Image:Prokaryote cell diagram.svg, which was also made by LadyofHats. Besides general appearance changes, this version adds plasmids and pili, and notes that DNA is circular. Latina: Diagramma cellulae naturalis prokaryoticae. Adobe Illustratore factaerat. (Photo credit: Wikipedia)
Schematical structure of a molecule of cyclic ...
Schematical structure of a molecule of cyclic di-GMP. The guanine (blue), ribose (red) and phosphate (green) have been bonded through dehydration. (Photo credit: Wikipedia)

I’m not a scientist at the bench anymore. My wife told me I had to stop playing and get a real job (a.k.a. graduate). However, I have very fond memories of my days studying chemotaxis. I will discuss that tomorrow in the second installment of My Tiny Highlight (MyTH) series. Bacteria, despite all modes of intimidation, do not follow our commands. They dance to the beat of a different drum, internal programming.  Following the scientific method is easy but hard. You can make observations all you want (in my case 6 and half years and over 40 hours of video), but describing why things with the cell are happening or how they happen is a process. Finding explanations for what you observe and designing experiments to test them teaches humility because inevitably the cells will prove you wrong.

There is not much bravado in science. Failure is much more common than success and I would not have it any other way. I learned ten times more from failure than success. My dissertation project was split into two main goals dealing with two different proteins within a single bacterium, let’s call them protein1 (due to embargo and not published yet) and Tlp1 (since one paper is already published). It took 4 years of mostly failure with P1 to open my eyes and look outside the box. Breakthrough! Tlp1 was more straight forward, at least I thought at first. I still failed to explain my observations for a few years. Once I started visualizing the inside of the cell, with all its organized chaos, I started to be more creative in my hypotheses. Ultimately, we discovered a sort of paradox to everything found in the literature about the bacterial second messenger cyclic-di-GMP (c-di-GMP). I can’t wait for it to be published.

Grad school taught me a lot. I learned that if you love what you do, it doesn’t seem like work. Most of all, I learned that failure is a good thing because it takes us outside the box which is usually where the correct answers are.

MyTH: A new weekly series about one bacterial species. First Post: Escherichia coli

This thought came to my head as I couldn’t sleep last night. My Tiny Highlight (MyTH) will be weekly and will showcase interesting or useful bacteria. For the first installment, I will focus on the gold standard of biology; Escherichia coli or E. coli. E. coli was discovered in 1885 by a German doctor in feces of healthy people. He called it Bacterium coli commune because it was found in the colon. The classification system of bacteria was much different before the ability to sequence DNA as novel bacteria were initially classified and named by their shape and motility. The name later changed to Bacillus coli before finally being reclassified and named Escherichia coli after the original discoverer. How would you like it if someone named a bacteria from feces after you?

E. coli receives a bad reputation thanks to pathogenic strains that force recalls of all kinds of food products. However, those strains are very uncommon as E. coli is one of the most abundant species found in the GI tract of mammals. Also, without this bacterium, many of the scientific discoveries of the past 50 years would not be possible including solving protein 3D structures, mass production of insulin, and understanding signal transduction; the process of a cell sensing surrounding signals or cues and responding to them in a way that is favorable for the cell. One reason E. coli was such a well suited model organism is the doubling time or time to divide one cell into two daughter cells. A doubling time of only 20 minutes means in less than 48 hours, the mass of E. coli cells would roughly be equal the the mass of Earth and have the combined volume equalling a 1 meter thick layer of bacteria covering the entire surface of Earth (including oceans). This is incredible and gives E. coli a major advantage over slower growing bacteria.

I want to discuss, briefly, a major influence of mine. Julius Adler was born in Germany and became a lover of Nature as a child. He was fascinated with butterflies. adler

His lifelong passion has been behavior of living things. Luckily, he spent most of his professional career studying chemotaxis in E. coli although he now studies fruit flies. Adler is known as the father of chemotaxis, or the movement of a cell in response to sensing chemical signals. His landmark early papers in the journal Nature about chemotaxis in E. coli in 1966 and his later paper on the chemoreceptors, the proteins that interact with the surrounding chemicals, in E. coli laid the foundation that maid the chemotaxis system of E. coli the best characterized signaling pathway in Biology. In regards to chemotaxis, however, E. coli is on the simplistic side of the scale. For example, E. coli has 5 chemoreceptors and 1 chemotaxis operon, or a stretch of genes that are transcribed into RNA together but lead to distinctly different proteins that usually interact with each other. Through the explosion of genome sequencing, scientists can scan newly sequenced bacteria genomes for chemotaxis genes. The average number of chemoreceptor genes is roughly 5 times more than E. coli (~25) and it is more common for bacteria to harbor multiple chemotaxis operons suggesting most bacteria have evolved to use chemotaxis for regulate more than the motility behavior in these cells.

Let’s think a minute about why E. coli is ‘stupid’ compared to other bacteria. By ‘stupid’ I mean, they have less capacity to integrate signals from their surroundings into a cell response. Why doesn’t E. coli have 25 chemoreceptors, for example? For the answer, we just need look at where this microbe is found. The GI tract of mammals is fairly constant meaning there is less need to scavenge for a new home or adjust to changes in temperature or nutrients. We as mammals have no problems eating meaning E. coli has no problem eating as well. How about the other sequenced bacteria? They predominantly live in more variable environments like soil or oceans where is would be to their advantage to be able to sense a lot of chemicals or nutrients in their surroundings. Therefore, through evolution, they have acquired new abilities to sense through duplicating genes and mutating DNA favorably. Changing only a few nucleotide bases (A,C,G,T) could mean acquiring the ability to physically interact with different environmental chemicals that could serve as an energy source. Nature is awesome and she knows how to keep us, as observers, guessing.

You may feel I am biased about chemotaxis ( I am). This was my dissertation work in another bacterium. Check back next week when I will highlight a little known (publicly) soil bacterium, Azospirillum brasilense. If you have any comments, questions, or suggestions PLEASE LET ME KNOW!

 

Recommended reading about Julius Adler.

Wanted: A Nation of Bill Nyes. Making science mainstream, fun, and relevant. Part 4. « Taking Science to the People

Wanted: A Nation of Bill Nyes. Making science mainstream, fun, and relevant. Part 4. « Taking Science to the People

In my humble opinion, keeping a child’s curiosity and imagination alive is a major step towards having real progress in attitudes and participation in STEM education. I personally wanted to be a doctor growing up. I was fascinated with how all cell types worked together. The checks and balances. As I grew older, in came the question of what specialty to go into as a medical professional. Knowing my interests, it seemed no ‘specialty’ was specialized enough. Then while working at a summer internship at the Oak Ridge National Laboratory, I went into an office with the Biochemical Pathways wall poster.
Metabolic_Pathways_for_plotter_landscape_quantized.png
I could not take my eyes off of this masterpiece. To me, this poster symbolized life at the smallest scale but yet so sophisticated and precise; not to mention the signal transduction pathways that mediate the pathways output at any given time. I had found my calling. This visualization of what I had been taught in biology classes at all levels and biochem classes in college came to fruition.
For others, I’m sure it is different and I’m sure it’s not for everyone. The goal, inspire as many as possible to explore their curiosity of how life works and how they could make it better. Now the question, how do we do it?

Wanted: A Nation of Bill Nyes. Making science mainstream, fun, and relevant. Part 4.

In my humble opinion, keeping a child’s curiosity and imagination alive is a major step towards having real progress in attitudes and participation in STEM education. I personally wanted to be a doctor growing up. I was fascinated with how all cell types worked together. The checks and balances. As I grew older, in came the question of what specialty to go into as a medical professional. Knowing my interests, it seemed no ‘specialty’ was specialized enough. Then while working at a summer internship at the Oak Ridge National Laboratory, I went into an office with the Biochemical Pathways wall poster.

Metabolic_Pathways_for_plotter_landscape_quantized.png

I could not take my eyes off of this masterpiece. To me, this poster symbolized life at the smallest scale but yet so sophisticated and precise; not to mention the signal transduction pathways that mediate the pathways output at any given time. I had found my calling. This visualization of what I had been taught in biology classes at all levels and biochem classes in college came to fruition.

For others, I’m sure it is different and I’m sure it’s not for everyone. The goal, inspire as many as possible to explore their curiosity of how life works and how they could make it better. Now the question, how do we do it?