Protein Structure Part 2: How and Why Do Proteins Fold?

[Music] Hi! Welcome to Part 2 of our pair of videos about
amino acids and protein structure. In Part 1 of this video,
you learned where proteins are found, the range of things they do, and about
the amino acids that make them up. In class you’ve learned about Beau, the puppy whose coat became curly as he
grew from a puppy to a young adult dog. In this video, we’ll talk about how and why
proteins fold into a variety of shapes that can do a variety of jobs. By the end, you’ll understand better
what happened to Beau. Don’t worry, it’s nothing bad. Just a normal part of Beau growing up! We already know that proteins have
a lot of different functions. How is that possible? How can proteins built from just 20 amino
acids do so many different things? To answer that question, let’s look more closely at the structure of
two proteins: actin and keratin. Actin is an example of a globular protein, which means the overall shape of the protein
is more spherical than elongated. Globular proteins can work alone, or in groups. For example, thousands of individual globular
actin protein molecules will come together to form a single actin microfilament. Just as amino acids are the building
blocks of larger proteins, the individual actin proteins are monomer
building blocks for larger microfilaments. Even though they have very different shapes,
both actin and keratin proteins, and in fact all proteins, start out
looking pretty much the same. All proteins are made up of long,
unbranched chains of amino acids. The types and order of the amino acids
in a protein chain is determined by the DNA in the
gene that codes for that protein. The actual sequence of amino acids in the
chain is called a protein’s primary structure. A straight, unfolded chain of amino acids
is almost completely inactive. The chain has to fold into a particular shape
to perform its proper functions. What shape it forms depends on the order
of amino acids in the primary structure. If a protein cannot fold properly,
it will not perform its normal function correctly. In the first step of protein folding, hydrogen bonds form between atoms in
the main peptide backbone of the chain. These hydrogen bonds make some regions of
the protein fold into specific shapes. For example, in this protein the amino group
of one amino acid is hydrogen bonding to the C=O group four amino acids
away in the primary sequence. As a result, this region of the protein folds
into a short, rod-like shape called an alpha helix. Hydrogen bonding between different pairs of
atoms in the peptide backbone can create other shapes, like beta sheets, beta barrels, bends, loops,
and even fingers. These commonly seen shapes are what we refer
to as the secondary structure of a protein. For now, alpha helices and beta sheets are the most
important secondary structures you need to know about. Secondary structure is just a small part
of the overall shape of a protein. Just because a protein has alpha helices,
for example, that does not mean the entire final
complete protein has to be rod-shaped. The complete, final 3-dimensional shape of
one peptide chain in space is called its tertiary
structure. Here is a ribbon model of an average size
protein that contains some rod-like alpha helices, beta sheets, bends, and other shapes. Their exact position and the final 3-dimensional
shape of the tertiary structure depends on a combination of
covalent and non-covalent interactions. So what are these interactions? First, the backbone of a protein can’t bend
in every possible direction. Parts of the molecule can rotate around
the carbons and nitrogens, but the bonds themselves do not bend. Hydrogen bonds are back, but now they form
between side groups of polar amino acids. Hydrophobic interactions bring together
side-groups of non-polar amino acids. Two cysteine amino acids in a protein
can form a covalent bond between groups that is called a disulfide bond. Positively and negatively charged amino
acid side groups can form ionic bonds. There is one final level of structure,
called quaternary structure. Proteins rarely work alone. Often two or more proteins must join together. The individual proteins, or subunits, can be copies of the same protein,
or two or more different proteins. There even can be non-protein
cofactor molecules in the complex. Here is an example of a quaternary structure. It is a single hemoglobin complex,
the molecule which carries oxygen in blood. Each red blood cell is packed with nearly
300 million of these complexes. Each hemoglobin complex is made up
of four protein molecules, and four non-protein cofactor molecules. There are two subunits of alpha globin protein
in blue, two subunits of beta globin protein in red, and four molecules of heme in green. This entire complex has a large, approximately
spherical shape. The same covalent bonds
and non-covalent interactions that determine tertiary structure
of individual proteins also hold a complex of proteins together
in their final three-dimensional shape. These interactions include hydrogen bonding,
hydrophobic interactions, ionic interactions, and covalent bonds. There’s also an additional non-covalent interaction
that occurs between protein molecules that have complementary shapes: van der Waals forces. Okay, so we know what gives a protein its
shape. If we change these molecular interactions
and forces in any way, we change how the proteins fold, pack together,
and interact with other proteins. How do we put all of this information to work? You learned before that hair, nails, horn, and the outer layers of skin are made up
almost entirely of keratins. What we didn’t explain before is that cells
put slightly different keratins in each of these
places. Both Marcy’s skin and mine contain
mainly soft pliable keratin fibers. My fingernails and her horn are made
up of keratin fibers too. So is our hair. Now how can organisms create structures
with such different properties as skin, nails, and hair, using the same types of protein,
in this case, keratin? Nails, horns, and hair are all secreted
by cells similar to skin cells. To create harder or softer structures,
these cells do one of two things: change the type of keratin proteins secreted, or they change how the proteins are packed
together. Different keratin proteins have slightly different
amino acid sequences in their primary structure. The different primary sequences change…
you guessed it… the inter – and intramolecular forces
that give the proteins their individual shapes, and that brings individual proteins together in larger protein complexes with different properties. If you look at nearly any structure in complex
organisms, you will find proteins being arranged in different
ways to produce different properties. Let’s look at hair, a feature found in all
mammals. Only the cells at the root of a hair,
within the skin, are alive. The visible shaft of each hair consists of
non-living materials produced by those cells. Depending on the species and body location,
hair is made up of 65 to 95% keratin. The remainder consists of surface lipids,
nuclear remnants, carbohydrates and some inorganic salts. A single hair is surprisingly complex. Each hair ranges in size from
10 to 100 micrometers in diameter. Cut in cross section, it can be cylindrical,
oval, or strongly flattened. Each hair has an outer layer or cuticle
composed of plate-like, overlapping dead cells, and a fibrous inner
cortex. Both the cuticle and the cortex contain
tightly packed keratin filaments. They are embedded in a gelatin-like matrix
of intermediate filament associated proteins
(IFAP). The arrangement is very similar to the
fiberglass used to make boats. Unlike fiberglass though, the keratin fibers
and matrix protein in hair are very flexible. Nearly all keratins, including those in hair, are 1 to 1 dimers of a
Type I and a Type II keratin molecule. Type I keratins also are called the acidic
keratins. Type II keratins also are called the basic
keratins. Acidic and basic keratins are so named
because they have relatively high concentrations of acidic and basic amino acid residues in the
head and tail regions of the keratin monomers. The head and tail domains of the monomers
control packing and organization into larger structures. The rod region is chemically
similar across all keratin types. It is the part of the protein where the
two keratin monomers fold around each other. Each monomer is an alpha helix,
and they form a helix again as they fold together. This kind of structural organization is called
a coiled-coil. At the molecular level, hydrophobic interactions make individual
keratin molecules combine into coiled coils. To make that coil more stable, keratin proteins contain high levels of the
sulfur-containing amino acid cysteine. Once the coiled coil forms,
cysteine disulfide bonds link the individual keratin monomers together,
forming more stable chemically resistant structures. Keratins also are unusual in that three amino
acids- tryptophan, histidine, and methionine – are found at very, very low concentrations. Tryptophan may be entirely absent from the
keratins found in some kinds of sheep wool. Now that you know more about how
proteins fold and organize into structures, go back and work through the rest of the case,
and find out what happened to Beau. [Music]