I have sat on this long enough. It’s not like a have anything else going on right now (except the birth of a son in a month, syllabus to write, classes to prepare, evaluations to do, data to journal, …). Introducing:
Here are the details presently. I and anyone willing to help will scour the journals of our respective fields and choose those we feel need to be disseminated to the larger public. In a short synopsis (abstract if you will), an overview of the article and why it is important will be written and deposited here. Details will be worked out on how to submit the abstracts in the near future.
Now is the time to act (or later if now is not convenient)!
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.
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?
Li and Stock. (2009) Biol. Chem. 390: 1067-1096. DOI 10.1515/BC.2009.133
This past Tuesday, something mysterious and amazing happened. My wife noticed a strange deposit into our bank account; a large deposit: $1,400. She asked when I was supposed to be paid for something I was working on and I told her not until later. This deposit piqued both our curiosities. What was it? Why was it in there? Who put it there? I started investigating; researching as much as I could. I was able to find out it was $1,400 cash, which bank branch and what time the money was put in. Paranoid it was some scam perpetrated to clean out our bank account, my wife wanted me to call the bank to inquire. So, Wednesday morning, I called. Long story short, my wife received a call Wednesday afternoon from a bank employee saying someone anonymously deposited money in our account because they thought we should have it. What? To say the least, we were humbled and astonished. The curiosity has not gone away. We are still trying to figure out who this saint(s) is.
This mystery made me think; it is eerily like the field of science. The path to discovery in any science discipline begins with something very simple, an observation. My wife observed a strange deposit into our bank account. Observations lead to curiosity and ultimately yield questions. What was this deposit? Why was it there? Who put it there? Explanations or answers to the questions are developed.These explanations, or hypotheses, have their validity tested through experiment or some action. My wife’s initial explanation was that someone deposited it to somehow gain access to our account to clean it out. My action of calling the bank to report the deposit as not originating from the wife or myself was partly to make sure the deposit was legitimate and not some clever scam. Through experiment or action, facts are gathered to support the explanations or rule them out. The fact a bank employee called to let us know the deposit was from an anonymous ‘Good Samaritan’ ruled out the hypothesis of the scam. Scientific discovery ultimately leads to more observations, curiosity, questions, and hypotheses.
For my wife and I, the discovery that someone thought so highly of us to give us any amount of money has only fueled the mystery. The main question now is, who did it? Unlike any good mystery, or science for that matter, we may never find out.
This post is dedicated to my family’s ‘Good Samaritan’. Thank you…
Patrons: metabolites/compounds/substrates and products
Managers: two-component proteins to regulate gene transcription
Employee list: genome
Copy machine: DNA replication machinery
So, in the last part our restaurant was going great and we opened up a new restaurant with the same employee list among other things. The two restaurants are now independent of each other and are free to act accordingly.
What if things change and times are not going as well? The overall number of patrons drastically decreases, not enough electricity (ATP) to run the restaurant or running water (redox potential)? What if disaster is about to strike? How can the restaurant prepare all the managers, employees, the building, the doors, the patrons for it?
Luckily the restaurant has a monitoring system that can quickly make sure the restaurant will be ready for anything that comes its way. The monitoring system can take snapshots of all data generated by the restaurant: power supply, water supply, patron count, employee count, conditions outside the restaurant like weather or competing restaurants. The monitoring system is the bacterial second messenger systems. With the support of the managers, the monitoring system can instantaneously keep track of all variables and make changes as needed.
The system is detecting the start of a drought. This drought will lower the number of patrons coming and going from the restaurant. The drought will also change the available electricity and water supply of the restaurant. The monitoring system sounds the alarm, a message is sent over the intercom for all the managers and employees to hear and react to. The intercom message alerts some managers to call in additional employees while telling others to stop their work. Some employees take on a new job in preparation for the drought. The intercom message is the bacterial second messenger cyclic-di-GMP. The entire restaurant begins preparations for the drought so it can survive until better times are present. Other than changes to managers and employees, some new employees are called in to prepare the building itself. Perhaps to change the number of doors. The employees may also change the exterior of the building to better withstand the drought like changing a wood exterior to a brick or stucco one. The brick or stucco are the exopolysaccharides, complex sugars on the exterior of the cell that can serve as protection or to help cells adhere to each other to ride out the hard times together.
When times change, the restaurant has to be able to change with them. That is why these restaurants have been in business for ~3 billion years and still going strong.
Many say storytelling in science is a great way to describe complex material in an understandable way for the masses. In this post, I will try to use an analogy to illustrate the complexity of a typical motile bacterial cell.
Microbial Physiology through Storytelling
If there is anything Americans know, it’s food. We are a nation obsessed with food and frequent restaurants on a regular basis.
Imagine your favorite restaurant as one huge bacterial cell.
When I travel to another city, I can’t rely on habit to guide me to a restaurant for dinner. I have to search for it while driving down the road. In order to know when I have found the restaurant I am searching for, I must rely on signs telling everyone what the restaurant is. The sign is a way to recognize and identify the building as i) a restaurant and ii) the specific type of restaurant. Bacteria do the same. They have ‘signs’ (proteins and other molecules) attached to the outside of the cell that lets other cells around identify what the cell is. I go into the restaurant through a door that allows patrons to move in and out of the building like bacteria have gates or channels that allow molecules to move in and out of the cell. Almost always, patrons are different leaving than they were when entering the restaurant; filled with yummy food they consumed and perhaps stopping to make a deposit in the waste room before leaving. Many molecules that leave a cell are different than those that enter. The workers of the restaurant have to keep track of the number of patrons entering and leaving the building to efficiently serve the patrons. Each employee has a specific job to do for very specific patrons. The employees have to identify their patrons and serve them as described by the bosses. Bacteria have an array of workers (proteins and protein complexes) that have very specific job descriptions depending on the patrons (substrates and product molecules) present in the cell. The restaurant survives by serving as many patrons as possible efficiently and correctly just as a cell must survive by responding correctly and quickly to everything in its environment.