We often think of proteins as nutrients in the food we eat or the main component of muscles, but proteins are also microscopic molecules inside of cells that perform diverse and vital jobs. With the Human Genome Project complete, scientists are turning their attention to the human “proteome,” the catalog of all human proteins. This work has shown that the world of proteins is a fascinating one, full of molecules with such intricate shapes and precise functions that they seem almost fanciful.
A protein’s function depends on its shape, and when protein formation goes awry, the resulting misshapen proteins cause problems that range from bad, when proteins neglect their important work, to ugly, when they form a sticky, clumpy mess inside of cells. Current research suggests that the world of proteins is far from pristine. Protein formation is an error-prone process, and mistakes along the way have been linked to a number of human diseases.
The wide world of proteins:
There are 20,000 to over 100,000 unique types of proteins within a typical human cell. Why so many? Proteins are the workhorses of the cell. Each expertly performs a specific task. Some are structural, lending stiffness and rigidity to muscle cells or long thin neurons, for example. Others bind to specific molecules and shuttle them to new locations, and still others catalyze reactions that allow cells to divide and grow. This wealth of diversity and specificity in function is made possible by a seemingly simple property of proteins: they fold.
Proteins fold into a functional shape
A protein starts off in the cell as a long chain of, on average, 300 building blocks called amino acids. There are 22 different types of amino acids, and their ordering determines how the protein chain will fold upon itself. When folding, two types of structures usually form first. Some regions of the protein chain coil up into slinky-like formations called “alpha helices,” while other regions fold into zigzag patterns called “beta sheets,” which resemble the folds of a paper fan. These two structures can interact to form more complex structures. For example, in one protein structure, several beta sheets wrap around themselves to form a hollow tube with a few alpha helices jutting out from one end. The tube is short and squat such that the overall structure resembles snakes (alpha helices) emerging from a can (beta sheet tube). A few other protein structures with descriptive names include the “beta barrel,” the “beta propeller,” the “alpha/beta horseshoe,” and the “jelly-roll fold.”
These complex structures allow proteins to perform their diverse jobs in the cell. The “snakes in a can” protein, when embedded in a cell membrane, creates a tunnel that allows traffic into and out of cells. Other proteins form shapes with pockets called “active sites” that are perfectly shaped to bind to a particular molecule, like a lock and key. By folding into distinct shapes, proteins can perform very different roles despite being composed of the same basic building blocks. To draw an analogy, all vehicles are made from steel, but a racecar’s sleek shape wins races, while a bus, dump truck, crane, or zamboni are each shaped to perform their own unique tasks.
Why does protein folding sometimes fail?
Folding allows a protein to adopt a functional shape, but it is a complex process that sometimes fails. Protein folding can go wrong for three major reasons:
1: A person might possess a mutation that changes an amino acid in the protein chain, making it difficult for a particular protein to find its preferred fold or “native” state. This is the case for inherited mutations, for example, those leading to cystic fibrosis or sickle cell anemia. These mutations are located in the DNA sequence or “gene” that encodes one particular protein. Therefore, these types of inherited mutations affect only that particular protein and its related function.
2: On the other hand, protein folding failure can be viewed as an ongoing and more general process that affects many proteins. When proteins are created, the machine that reads the directions from DNA to create the long chains of amino acids can make mistakes. Scientists estimate that this machine, the ribosome, makes mistakes in as many as 1 in every 7 proteins! These mistakes can make the resulting proteins less likely to fold properly.
3: Even if an amino acid chain has no mutations or mistakes, it may still not reach its preferred folded shape simply because proteins do not fold correctly 100% of the time. Protein folding becomes even more difficult if the conditions in the cell, like acidity and temperature, change from those to which the organism is accustomed.
A failure in protein folding causes several known diseases, and scientists hypothesize that many more diseases may be related to folding problems. There are two completely different problems that occur in cells when their proteins do not fold properly.
One type of problem, called “loss of function,” results when not enough of a particular protein folds properly, causing a shortage of “specialized workers” needed to do a specific job. For example, imagine that a properly folded protein is perfectly shaped to bind a toxin and break it into less toxic byproducts. Without enough of the properly folded protein available, the toxin will build up to damaging levels. As another example, a protein may be responsible for metabolizing sugar so that the cell can use it for energy. The cell will grow slowly due to lack of energy if not enough of the protein is present in its functional state. The reason the cell gets sick, in these cases, is due to a lack of one specific, properly folded, functional protein. Cystic fibrosis, Tay-Sachs disease, Marfan syndrome, and some forms of cancer are examples of diseases that result when one type of protein is not able to perform its job. Who knew that one type of protein among tens of thousands could be so important?
Proteins that fold improperly may also impact the health of the cell regardless of the function of the protein. When proteins fail to fold into their functional state, the resulting misfolded proteins can be contorted into shapes that are unfavorable to the crowded cellular environment. Most proteins possess sticky, “water-hating” amino acids that they bury deep inside their core. Misfolded proteins wear these inner parts on the outside, like a chocolate-covered candy that has been crushed to reveal a gooey caramel center. These misfolded proteins often stick together forming clumps called “aggregates.” Scientists hypothesize that the accumulation of misfolded proteins plays a role in several neurological diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and Lou Gehrig’s (ALS) disease, but scientists are still working to discover exactly how these misfolded, sticky molecules inflict their damage on cells.
One misfolded protein stands out among the rest to deserve special attention. The “prion” protein in Creutzfeldt-Jakob disease, also known as mad cow disease, is an example of a misfolded protein gone rogue. This protein is not only irreversibly misfolded, but it converts other functional proteins into its twisted state.
How do our cells protect themselves from misfolded proteins?
Recent research shows that protein misfolding happens frequently inside of cells. Fortunately, cells are accustomed to coping with this problem and have several systems in place to refold or destroy aberrant protein formations.
Chaperones are one such system. Appropriately named, they accompany proteins through the folding process, improving a protein’s chances of folding properly and even allowing some misfolded proteins the opportunity to refold. Interestingly, chaperones are proteins themselves! There are many different types of chaperones. Some cater specifically to helping one type of protein fold, while others act more generally. Some chaperones are shaped like large hollow chambers and provide proteins with a safe space, isolated from other molecules, in which to fold. Production of several chaperones is boosted when a cell encounters high temperatures or other conditions making protein folding more difficult, thus earning these chaperones the alias, “heat shock proteins.”
Another line of cell defense against misfolded proteins is called the proteasome. If misfolded proteins linger in the cell, they will be targeted for destruction by this machine, which chews up proteins and spits them out as small fragments of amino acids. The proteasome is like a recycling center, allowing the cell to reuse amino acids to make more proteins. The proteasome itself is not one protein but many acting together. Proteins frequently interact to form larger structures with important cellular functions. For example, the tail of a human sperm is a structure composed of many types of proteins that work together to form a complex rotary engine that propels the sperm forward.
Future research about protein folding and misfolding:
Why is it that some misfolded proteins are able to evade systems like chaperones and the proteasome? How can sticky misfolded proteins cause the neurodegenerative diseases listed above? Do some proteins misfold more often than others? These questions are at the forefront of current research seeking to understand basic protein biology and the diseases that result when protein folding goes awry.
The wide world of proteins, with its great assortment of shapes, bestows cells with capabilities that allow for life to exist and allow for its diversity (e.g., the differences between eye, skin, lung or heart cells, and the differences between species). Perhaps for this reason, the word “protein” is from the Greek word “protas,” meaning “of primary importance.”
–Contributed by Kerry Geiler, a 4th year Ph.D student in the Harvard Department of Organismic and Evolutionary Biology
For More Information:
A video portrayal of the fantastic multitude of protein shapes:
< http://multimedia.mcb.harvard.edu/ >
Recent advancements in protein folding:
< http://www.scientificamerican.com/blog/post.cfm?id=scientists-observe-protein-folding-2010-02-28 >
Does the forgoing information have anything to do with the unfolding of the amyloid proteins in our bodies?
Very instructive and lucid article on a subject I am very curious to learn. Is there a protein-folding code we need to search beyond the DNA code? Something hidden in the long aminoacid chains that specifies various folding patterns? We also need to know about any epigenetic control of the protein processing in a cell and also in its intercellular moves.
Current editing of DNA and RNA structures will perhaps tell us more about the genetic code of life at organismal level.
It seems like a complex universe in our body but few doctors (other than specialists) understand what goes on when people fall sick or contract diseases. Many died without even knowing what caused it.
Thanks for the informative narrative about protein folding which I read it for the first time.
Sincerely hope there will breakthrough in such medical research to save more lives!
Unbelievably good article. Thanks for explaining it simple enough for an average Joe like me to understand. Blew my mind.
Thank you,
For sharing such an informative article and guiding people with the best of your knowledge about protein
I am pretty sure this will be going to add value to them.
Alpha-Synuclein PET Tracer Discovery | Parkinson’s Disease – Where can I find out the latest regarding PD? RJ Benitz, PharmD, Parkinson’s patient
How do newly produced proteins fold so quickly given that the process of the n amino acids in any protein will not be achievable even at the speed of light if we rely just on the laws of physics?
Is misfolding tied to Diabetes?