Protein Folding - Online Tutor, Practice Problems & Exam Prep

Protein folding occurs in four levels: primary, secondary, tertiary, and quaternary structures. The primary structure is the linear sequence of amino acids linked by peptide bonds. Secondary structures include alpha helices and beta sheets formed by hydrogen bonds. Tertiary structure refers to the 3D conformation of a single polypeptide, involving motifs and domains that dictate function. Quaternary structure involves multiple polypeptide chains, or subunits, linked by non-covalent interactions. Additionally, unstructured regions provide flexibility, allowing proteins to interact with various targets, highlighting the complexity and functionality of protein structures.

Primary Structure

Hi. In this video, we are going to talk about protein folding. So, there are four levels of protein folding, and the first one that we're going to talk about is the primary structure. So what is the primary structure? The primary structure is the linear sequence of amino acids in a polypeptide chain. This is just the order of amino acids. This is important to know because the R groups of the sequence of amino acids give the information for folding, or otherwise known as the three-dimensional conformation of the protein structure. The amino acids themselves are attached via covalent peptide bonds, which hold the amino acids together to form the primary structure. If we're just looking at what the primary structure is, you have this linear sequence of amino acids going this way. They're attached through covalent peptide bonds, and each one of these amino acids has an R group which gives the protein its unique properties. So, let's move on.

Secondary Structure

So in this video, we're going to talk a lot about the secondary structure of amino acids or the secondary structure of proteins. The secondary structure refers to the local, nearby, or close structures formed by the polypeptide backbone. There are two main ones that we want to focus on. The first is an alpha helix. An alpha helix involves hydrogen bonds made between every 4th amino acid. This allows for this rigid cylinder to form that can either be right-handed or left-handed. Essentially, it's a helix of proteins that forms in this rigid cylindrical structure. This type of helix is found a lot of times in skin proteins.

Now, the second one is the beta sheet. This involves hydrogen bonds made between segments of the polypeptide chain, but they're arranged side by side. They can be parallel, where two chains are going in the same direction, or antiparallel, with two chains going in opposite directions. Let me scroll up so you can see that. This type of pattern is abundant in skin proteins. So let's look at this so we can see what it actually looks like. Here you have your alpha helix, the cylindrical chain made by hydrogen bonds between every 4th amino acid. Then you have the beta sheet. These are hydrogen bonds made between sheets of the polypeptide backbone. These can run parallel or antiparallel. The ones you're seeing here are antiparallel because one is going in this direction and one is headed in that direction. So that's secondary structure. Let's move on.

Tertiary Structure

So, in this video, we're going to talk about tertiary structure, which is actually referring to the 3D conformations formed by a single polypeptide chain. These conformations can be functional or structural. There's a lot of information behind me, a lot of vocabulary, and just sort of understanding this. But, as we go through all the different levels of protein structure, of course, they have to get more complicated. There are a few types of really, two kinds of structural things that we need to know about when referring to structural or tertiary structure. The first is structural motifs. These are two or more secondary structures that work together to form a 3D structure. For instance, one of these is called a coiled coil. This is two to three alpha helices. Those are the secondary structures we're talking about in this definition. Two to three alpha helices wrap around each other and form this really stable motif. That's an example of one. There are a couple of others that you may read about in your books, called a helix turn helix or a helix loop helix. These are named based on how these multiple helices or how these secondary structures come together to form this 3D tertiary structure. Each structural motif usually has a specific function in the protein.

Now, the second type of tertiary structure I want to talk about is protein domains. These are larger segments of the polypeptide chain, around 40 to 350 amino acids. They can fold into independent stable structures. Like the motifs, each domain usually has a specific function. You may read about some of these domains, and they're usually commonly found in multiple proteins. The same domains can be found in multiple proteins. An example of this would be the SH2 domain, and it's found in over around 120 polypeptide chains. You don't need to know that domain right now. Just know it's an example of a domain that's found in multiple proteins. This happened because of a process called domain shuffling, which occurred throughout evolution to sort of link different protein domains in new combinations and new proteins. Domain shuffling is the reason that we have all these different domains sprinkled throughout different proteins. Domains are an extremely important feature of tertiary structure. They are found in two-thirds of proteins and contain actually more than one protein domain. So protein domains are really important.

Tertiary structure also forms two main protein types, fibrous protein and globular proteins. Fibrous proteins are proteins with an elongated shape, and globular proteins are sort of more globular; they're kind of more of a compact shape. So, if we're looking at what does a tertiary structure of our protein look like, here we go. You can see these sort of secondary structures here. The alpha helix, these beta sheets going throughout here. But the tertiary structure is how these all work together in a single polypeptide chain. You have multiple of these beta sheets. You have multiple alpha helices. And these all come together to create specific motifs or specific domains within the protein that forms this tertiary structure. So let's move on.

Quaternary Structure

So in this video, we're going to talk about the 4th protein folding level, which is the quaternary structure. This structure refers to a protein complex with more than one polypeptide chain. These are multimeric proteins. Remember, multimeric means they have more than one polypeptide chain, usually with two or more polypeptide chains, and each polypeptide chain is called a subunit. Each subunit can be identical or non-identical to other subunits. For instance, a homodimer is going to be a protein with two identical subunits, and a heterodimer will be a protein with two non-identical subunits. These polypeptide chains are linked through non-covalent bonds, but they can also be linked through disulfide bonds between the cysteines in each polypeptide chain, forming really stable multimeric proteins. If we were to look at what this looks like, we have our multimeric protein. And we have our four polypeptide chains, that's one, two, three, and four. They're all different colors. How these bind together and form together to create this single protein molecule is referred to as the quaternary structure. So now let's move on.

Unstructured Regions

So in this video, we're going to focus on a unique aspect of protein structure, and that's actually the unstructured regions. Unstructured regions can also be called disordered regions, and they really exist between ordered protein structures or domains. Unstructured regions are usually surrounded by other very ordered, systematic protein regions. And so the unstructured regions really provide flexibility to the protein structure and folding. They have, because they are not really ordered and they're not necessarily folding for anything, they can actually do all these different functional or structural aspects to them. One is that they can wrap around target proteins with really high specificity, but low affinity. They can scaffold proteins together. And nearly one third of eukaryotic proteins actually have unstructured regions in at least one polypeptide chain. And, actually, some of them can be found as the entire polypeptide chain. And these, if the entire polypeptide chain is this unstructured region, it's usually going to form an aggregate in the cytosol. So if we're looking at what an unstructured region looks like on a protein, you see here that in these colored regions are kind of structured. They form more complex structures, alpha helices, beta sheets. But these regions outside, outside of these ordered regions, are the unstructured regions. And they just don't fold into anything, and that gives them this flexibility to kind of do whatever the protein needs them to do. They're a really unique structure, but a very important one when talking about protein structure and folding. So now let's move on.

Match the following protein structures with their appropriate definitions 

i. Primary Structure _____________
ii. Secondary Structure _____________
iii. Tertiary Structure _____________
iv. Quaternary Structure _____________ 

a. 3D conformation of a single polypeptide chain 

b. Linear sequence of amino acids 

c. Folding of multiple polypeptide chains together 

d. Local structures of a single polypeptide chain

Okay, everyone, match the following protein structures with their appropriate definitions. Great practice question going over all the different structures within a protein that we learn. So primary, secondary, tertiary, and quaternary structure. We have to remember the main differences between these different structures within a protein. Remember, primary structure is going to be the first structure. What do we know about primary structure? It's going to be a string of amino acids attached to one another in a particular order. These are all amino acids, and they're going to have a unique order, a unique arrangement that creates a protein. Primary structure is going to be answer choice B: A linear sequence of amino acids. So, we're going to put B and cross that one out. Now that we have our linear sequence of amino acids in a particular order, what is secondary structure going to entail? Remember, that linear sequence of amino acids is going to form some structures within it, like alpha helices and beta pleated sheets. These are going to be part of the secondary structure. They're going to form from the sequence of amino acids creating local structures of a single polypeptide chain. That is answer choice D. So, alpha helices and beta pleated sheets are going to cross this one out. Let's do tertiary structure. Now that we have our amino acid sequence that has these small structures in it, like alpha helices and beta pleated sheets, what do we do next? We need to fold that polypeptide. This folding of a single polypeptide chain leads us to answer choice A, the 3D conformation of a single polypeptide chain, which is going to go for tertiary structure. The reason this is the correct answer is that tertiary structure only refers to a single polypeptide chain, not multiple polypeptide chains. Finally, we have quaternary structure. Remember, quaternary structure only applies to proteins that have multiple polypeptide chains. So, answer choice C is the correct answer because it says folding of multiple polypeptide chains together, and this is going to create a multimeric protein, a protein composed of multiple polypeptide chains. If the protein is composed of only one polypeptide chain, you will only have primary, secondary, and tertiary structure. However, if the protein is composed of more than one polypeptide chain, you will also have quaternary structure. Quaternary structure deals with how those different polypeptide chains interact with one another to create one protein complex. Okay, everyone. Let's go on to our next topic.

An alpha helix is a protein folding pattern that is classified under which of the following protein structures?

• A. Primary
• B. Secondary
• C. Tertiary
• D. Quaternary

A protein with 3000+ amino acids obtained a mutation that caused an amino acid change in a region of the protein that does not normally interact with other molecules. What type of effect could this cause?

• A. None, one amino acid change is not drastic enough to cause any kind of effect
• B. None, because the region of the mutation does not interact with any other molecules, the mutation would have no effect
• C. It could alter the protein's structure and therefore function
• D. It would cause translation to stop, and the protein would never be created

he entire sequence of the protein is used to form the protein's structure.

• A. True
• B. False

A coiled coil and an alpha helix are two terms for the same structure.

• A. True
• B. False

Here’s what students ask on this topic:

What is the primary structure of a protein?

The primary structure of a protein is the linear sequence of amino acids in a polypeptide chain. These amino acids are linked together by covalent peptide bonds. The sequence of amino acids determines the protein's unique properties and provides the information necessary for the protein to fold into its three-dimensional conformation. Each amino acid in the sequence has an R group, which contributes to the protein's overall characteristics and functionality.

What are the main types of secondary structures in proteins?

The main types of secondary structures in proteins are alpha helices and beta sheets. Alpha helices are formed by hydrogen bonds between every fourth amino acid, creating a rigid, cylindrical structure. Beta sheets are formed by hydrogen bonds between segments of the polypeptide chain arranged side by side. These can be parallel, with chains running in the same direction, or antiparallel, with chains running in opposite directions. Both structures are crucial for the protein's overall stability and function.

What is the tertiary structure of a protein?

The tertiary structure of a protein refers to the three-dimensional conformation formed by a single polypeptide chain. This structure includes various motifs and domains that contribute to the protein's function. Structural motifs are combinations of secondary structures, such as alpha helices and beta sheets, that form stable 3D structures. Protein domains are larger segments of the polypeptide chain that fold into independent, stable structures. The tertiary structure is essential for the protein's functionality and includes both fibrous and globular proteins.

What is the quaternary structure of a protein?

The quaternary structure of a protein refers to a complex formed by more than one polypeptide chain, known as subunits. These subunits can be identical or non-identical and are linked through non-covalent interactions or disulfide bonds. Examples include homodimers, with two identical subunits, and heterodimers, with two non-identical subunits. The quaternary structure is crucial for the protein's overall stability and function, allowing for complex interactions and activities.

What are unstructured regions in proteins?

Unstructured regions, also known as disordered regions, are parts of a protein that do not form a fixed three-dimensional structure. These regions exist between ordered protein structures or domains and provide flexibility to the protein. Unstructured regions can wrap around target proteins with high specificity but low affinity, scaffold proteins together, and contribute to various functional and structural roles. Nearly one-third of eukaryotic proteins have unstructured regions, highlighting their importance in protein function and interaction.