Chapter 6 Proteins: Secondary, Tertiary, and Quaternary Structure

Reginald H. GarrettCharles M. Grisham

Chapter 6Proteins: Secondary, Tertiary, and

Quaternary Structure

Outline

• What noncovalent interactions stabilize protein structure ?

• What role does the amino acid sequence play in protein structure ?

• What are the elements of secondary structure in proteins, and how are they formed ?

• How do polypeptides fold into three-dimensional protein structures ?

• How do protein subunits interact at the quaternary level of protein structure ?

Protein Structure and Function Are Linked

• The three-dimensional structures of proteins and their biological functions are linked by several relevant principles:• Function depends on structure.• 3o Structure depends on sequence (1o structure)

and on weak, noncovalent forces.• The number of protein folding patterns is large but

finite.• Structures of globular proteins are marginally

stable.• Marginal stability facilitates limited motion.• Motion enables function.

6.1 What Noncovalent Interactions Stabilize the Higher Levels of Protein Structures?

What are these noncovalent, “weak forces” ? What are the relevant numerical values for the

energy of these forces ?

• van der Waals: 0.4-4 kJ/mol • hydrogen bonds: 12-30 kJ/mol • ionic bonds: 20 kJ/mol • hydrophobic interactions: <40 kJ/mol

6.1 What Noncovalent Interactions Stabilize the Higher Levels of Protein Structure?

• Secondary, tertiary, and quaternary structure of proteins are formed and stabilized by weak forces (and in some cases by –S-S-).

• Hydrogen bonds are formed wherever possible.• Hydrophobic interactions drive protein folding.• Ionic interactions usually occur on the protein

surface.• Van der Waals interactions are ubiquitous.

Electrostatic Interactions in Proteins

Figure 6.1 An electrostatic interaction between a positively charged lysine amino group and a negatively charged glutamate carboxyl group.

Electrostatic Interactions in Proteins

Figure 6.1 An electrostatic interaction between lysine and glutamate side chains in IRAK-4, an enzyme that phosphorylates other proteins. The positively charged amino group (left) forms an ionic interaction with the negatively charged glutamate (right). Interleukin receptor

associated kinase 4 (IRAK4)

6.2 What Role Does the Amino Acid Sequence Play in Protein Structure?

All of the information necessary for folding the peptide chain into its "native” structure is contained in the primary amino acid structure of the peptide.

• Certain loci along the chain may act as nucleation points.

• Protein chain must avoid local energy minima.• Chaperones may help.

How do proteins recognize and interpret the folding information ?

6.3 What Are the Elements of 2o Structure in Proteins. How Are They Formed?

• The atoms of the peptide bond lie in a plane.• All protein structure involves the amide plane.• The resonance stabilization energy of the planar

structure is 88 kJ/mol. • A rotation about the C-N bond involves a twist

energy of 88 kJ/mol times the square of the angle of rotation.

• Rotation can occur about either of the bonds linking the alpha carbon to the other atoms of the peptide backbone.

Consequences of the Amide Plane

There are two degrees of freedom per residue for the peptide chain.

The angle about the Cα-N bond is denoted φ (phi). The angle about the Cα-C bond is denoted ψ (psi).

The entire path of the peptide backbone is known if all φ and ψ angles are specified.

Some values of φ and ψ are more likely than others.

Figure 6.2 The amide or peptide bond planes are joined by the tetrahedral bonds of the α-carbon.

The rotation parameters are φ and ψ. The conformations shown corresponds to φ= 180° and ψ= 180°.

Positive values of rotation for φ and ψ as viewed from Cα.

6.3 What Are the Elements of 2o Structure in Proteins. How Are They Formed?

Some Values of φ and ψ Are Not Allowed

Figure 6.3 Many of the possible conformations about an α-carbon between two peptide planes are forbidden because of steric crowding.

Steric Constraints on φ & ψ

Unfavorable orbital overlap precludes some combinations of φ and ψ

G. N. Ramachandran was the first to show the convenience of plotting phi, psi combinations from known protein structures.

φ = 0°, ψ = 180° is unfavorable φ = 180°, ψ = 0° is unfavorable φ = 0°, ψ = 0° is unfavorable

• The sterically favorable combinations are the basis for preferred secondary structures.


Figure 6.4 A Ramachandran diagram showing the sterically reasonable values of the angles φ & ψ. The shaded regions indicate particularly favorable values of these angles. Dots in purple indicate actual angles measured for 1000 residues (excluding glycine, for which a wider range of angles is permitted) in eight proteins.


Anti || β-sheet; || β- sheet; collagen; left handed α-helix

right handed α-helix; π-helix

α-helix = 3.613

π-helix =4.416

closed =50

Classes of Secondary Structure

Secondary structures are rotational arrangements about the alpha-C that are stabilized by hydrogen bonds:

• Alpha helices • Other helices • Beta sheet (composed of "beta strands") • Tight turns (aka beta turns or beta bends) • Beta bulge

The α-Helix

• First proposed by Linus Pauling and Robert Corey in 1951 (Read the box about Pauling on page 143).

• Identified in keratin by Max Perutz. • A ubiquitous component of proteins. • Stabilized by H bonds.

Hydrogen Bonds in Proteins

Figure 6.5 Schematic drawing of a hydrogen bond between a backbone C=O and a backbone N-H.

Hydrogen Bonds in Proteins

Figure 6.5 A hydrogen bond between a backbone C=O and a backbone N-H in an acetylcholine binding protein of a snail, Lymnaea stagnalis.

The α-Helix

Figure 6.6 Four different representations of the α-helix.

Numbers to Know

• Residues per turn: 3.6 • Rise per residue: 1.5 Angstroms. • Rise per turn (pitch): 3.6 x 1.5Å = 5.4 Angstroms.• The backbone loop that is closed by any H-bond

in an alpha helix contains 13 atoms. • φ = -60 degrees (-57o), ψ = -45 degrees (-47o). • The non-integral number of residues per turn was

a surprise to crystallographers.

The α-Helix

The α-Helix in Proteins

Figure 6.7 Two proteins that contain substantial amounts of α-helix.

The α-Helix Has a Substantial Net Dipole Moment

Figure 6.8 The arrangement of N-H and C=O groups (each with an individual dipole moment) along the helix axis creates a large net dipole moment for the helix. The numbers indicate fractional charges on respective atoms.

Exposed N-H and C=O groups at the ends of an α-Helix can be “capped”.

Figure 6.9 Four N-H groups at the N-terminal end of an α-helix and four C=O groups at the C-terminal end lack partners for H-bond formation. The formation of H bonds with other nearby donor and acceptor groups is referred to as helix capping. Capping may also involve appropriate hydrophobic interactions that accommodate nonpolar side chains at the ends of helical segments.

Amino acids can be classified as helix-formers or helix breakers

KeyH = forms helixB = breaks helix I = indifferentC = random coil

The β-Pleated Sheet

• The β-pleated sheet is composed of β-strands.• Also first postulated by Pauling and Corey,

1951. • Strands in a β-sheet may be parallel or

antiparallel. • Rise per residue: • 3.47 Angstroms for antiparallel strands.• 3.25 Angstroms for parallel strands.• Each strand of a β-sheet may be pictured as

a helix with two residues per turn.• φ = -139 degrees, ψ = +135 degrees.

Figure 6.10 A “pleated sheet” of paper with an antiparallel β-sheet drawn on it.


(a) Parallel and (b) antiparallel β-sheets.


The β-Turn

(aka β-bend, or tight turn)

• Allows the peptide chain to reverse direction. • Carbonyl C of one residue is H-bonded to the

amide proton of a residue three residues away. • Proline and glycine are prevalent in β-turns.• There are two principle forms of the β-turn, Type

I and Type II. • Can connect α-helix or β-sheet structures.

Figure 6.12 The structures of two kinds of β-turns (also called tight turns or β-bends). Four residues are required to form a β-turn. Left: Type I; Right: Type II.The plane of the peptide bond in back has rotated 180o.

The β-Turn

The β-Bulge

A disruption of normal H-bonding in the β-sheet structure due to insertion of an extra amino acid in one of the strands of either the antiparallel or parallel arrangement. This amino acid residue is not able to rotate into the required conformation for β-sheet.

As a result a bulge occurs in the strand with the nonconforming amino acid residue.

6.4 How Do Globular Polypeptides Fold into 3o Protein Structures?

Important principles about secondary structure:• Helices and sheets often pack close together.• Proteins fold so as to form the most stable

structures. • Stability arises from large numbers of

intramolecular hydrogen bonds and reduction in the surface area accessible to solvent that occurs upon folding.

• Note that hydrophobic groups tend to cluster together in the folded interior of the protein and many of the hydrophilic groups are on the surface (exterior) of the protein.

Fibrous Proteins

• Much or most of the polypeptide chain is organized approximately parallel to a single axis.

• Fibrous proteins are often mechanically strong.• Fibrous proteins are usually insoluble. • Usually play a structural role in nature.• Three types of fibrous protein are discussed

here:• α-Keratin contains –S-S-bridges• β-Keratin contains –S-S-bridges• Collagen contains NO –S-S-bridges

α-Keratin

• A fibrous protein found in hair, fingernails, claws, horns and beaks.

• The sequence consists of alpha helical rod segments (311-314 residue) capped with non-helical N- and C-termini.

• Primary structure of helical rods consists of 7-residue repeats: (a-b-c-d-e-f-g)n, where a and d are nonpolar.

• This structure promotes association of helices to form coiled coils.

Figure 6.13 The structure of α-keratin.

α-Keratin: an α-helical protein

The Coiled Coil – An Important Structural Motif in Proteins

The coiled coil is a bundle of α-helices wound into a superhelix.The left-handed twist of the structure reduces the number of resides per turn to 3.5, so that the positions of the side chains repeat every 7 residues.

Fibroin and β-Keratin: β-Sheet Proteins

Proteins that form extensive beta sheets

• These are found in silk fibers and bird feathers.• Alternating sequence:

Gly-Ala/Ser-Gly-Ala/Ser.... • Since residues of a β-sheet extend alternately

above and below the plane of the sheet, this places all glycines on one side and all alanines and serines on other side!

• This allows Gly on one sheet to mesh with Gly on an adjacent sheet (same for Ala/Ser).

Fibroin and β-Keratin: β-Sheet Proteins

Figure 6.14 Silk fibroin consists of a unique stacked array of β-sheets.

Collagen – A Triple Helix

Principal component of connective tissue (tendons, cartilage, bones, teeth)

• Basic unit is tropocollagen: • Three intertwined polypeptide chains (1000

residues each). Each strand is a left-handed helix and they form a right-handed triple coil.

• MW = 285,000, 300 nm long, 1.4 nm diameter. • Unique amino acid composition, including

hydroxylysine and hydroxyproline.• Hydroxyproline is formed by the vitamin C-

dependent prolyl hydroxylase reaction.


Figure 6.15 Hydroxylation of proline residues is catalyzed by prolyl hydroxylase.

Facts about its a.a. composition...

• Nearly one residue out of three is Gly. • Proline content is unusually high. • Unusual amino acids found: • 4-hydroxyproline • 3-hydroxyproline • 5-hydroxylysine • Pro and HyPro together make 30% of the

residues.



Hydroxyproline and hydroxylysine structures.

A case of structure following composition

• The unusual amino acid composition of collagen is unsuited for alpha helices or beta sheets.

• It is ideally suited for the collagen triple helix: three intertwined helical strands.

• Much more extended than alpha helix, with a rise per residue of 2.9 Angstroms.

• 3.3 residues per turn. • Long stretches of Gly-Pro-Pro/HyP.



Figure 6.16 Poly(Gly-Pro-Pro), a collagen-like right-handed triple helix composed of three left-handed helical chains.There are at least 16 collagen varients from 30 distinct chains.

Staggered arrays of tropocollagens

• Banding pattern in electronmicrographs (EMs) show a 68 nm repeat.

• Since tropocollagens are 300 nm long, there must be 40 nm gaps between adjacent tropocollagens (5 x 68 = 340 nm).

• 40 nm gaps are called "hole regions" - they contain carbohydrate and are thought to be nucleation sites for bone formation.

Collagen Fibers


Figure 6.17 In the electron microscope, collagen fibers exhibit alternating light and dark bands. The dark bands correspond to the 40-nm gaps between pairs of aligned collagen triple helices.

• Every third residue faces the crowded center of the helix - only Gly fits here.

• Pro and HyP suit the constraints of φ and ψ. • Interchain H-bonds involving HyP stabilize helix. • Fibrils are further strengthened by intrachain.

lysine-lysine and interchain hydroxypyridinium crosslinks.

• There are no disulfides in collagen.• Crosslinks are due to lysine residues.

Structural basis of the collagentriple helix

Collagen Crosslinking

Collagen crosslinks are due to lysine derivatives.

Hole regions in collagen fibrils may be the sites of nucleation for bone mineralization

A disaccharide of galactose and glucose is covalently linked to the 5-hydroxyl group of hydroxylysines in collagen by the combined action of galactosyltransferase and glucosyltransferase.The carbohydrate content of collagen varies from 0.4 – 12%. Its function is uncertain.

Globular Proteins Mediate Cellular Function

• Globular proteins are more numerous than fibrous proteins.

• The diversity of globular protein structures in nature reflects the remarkable variety of functions they perform.

• Functional diversity derives in turn from:• The large number of folded structures that

polypeptides can adopt.• The varied chemistry of the side chains of the 20

common amino acids.

Some design principles

• Helices and sheets make up the core of most globular proteins.

• Most polar residues face the outside of the protein and interact with solvent.

• Most hydrophobic residues face the interior of the protein and interact with each other

• Packing of residues is close. • However, ratio of VdW volume to total volume is

only 0.72 to 0.77, so empty space exists. • The empty space is in the form of small cavities.

Globular Proteins

Why does the protein core consist primarily of α–helices and β–sheets?

• The protein core is predominantly hydrophobic.• The highly polar N-H and C=O moieties of the

peptide backbone must be neutralized in the hydrophobic core.

• The extensively H-bonded nature of α-helices and β-sheets is ideal for this purpose.

Protein core versus protein surface

• The helices and sheets in the core of a globular protein are typically constant and conserved in sequence and structure.

• The protein surface is different in several ways.• Much of the surface is composed of loops and tight

turns that connect the helices and sheets of the core.• Thus the surface is a complex landscape of different

structural elements.• These surface elements can interact with small

molecules or with other proteins.• They are the basis for enzyme-substrate

interactions, cell signaling, and immune responses.

“Random coils” are not random

• The segments of a protein that are not helices or sheets are traditionally referred to as “random coil”, although this term is misleading:• Most of these segments are neither coiled or

random.• They are usually organized and stable, but don’t

conform to any frequently recurring pattern.• Random coil segments are strongly influenced

by side-chain interactions with the rest of the protein.

Globular Proteins

Figure 6.19 The structure of ribonuclease, showing elements of helix, sheet and random coil.

Protein surfaces are complex

Figure 6.20 The surfaces of proteins are complementary to the molecules they bind.

Waters on the Protein Surface Stabilize the Structure• The surface structure of a globular protein includes

water molecules.• The polar backbone and side chain groups on the

protein surface make H bonds with solvent water.• α-Helices on a protein surface are usually

amphiphilic, with polar and charged residues facing the solvent and nonpolar residues facing the interior.

• A helical wheel presentation can reveal the amphiphilic nature of an α-helix.

• Some α-helices are hydrophobic and buried in the protein interior.

• Some helices are polar and entirely solvent-exposed.

Waters on the Protein Surface Stabilize the Structure

Figure 6.21 The surfaces of proteins are ideally suited to form multiple H bonds with water molecules.

α-Helices May be Polar, Nonpolar or Amphiphilic

Figure 6.22 The so-called helical wheel presentation can reveal the polar or nonpolar character of α-helices.

Packing Considerations in Globular Proteins

• Secondary structures pack closely to one another and also intercalate with extended polypeptide chains.

• The sum of the van der Waals volumes of a protein’s amino acids divided by the total volume occupied by the protein is typically 0.72 to 0.77.

• These “packing densities” are similar to those of a collection of solid spheres.

• Thus, approximately 25% of the total volume of a protein is not occupied by protein atoms.

• Most of this volume is in the form of small cavities.• Such cavities provide flexibility for proteins and

facilitate conformation changes and protein dynamics.

Protein domains are nature’s modular strategy for protein design• Proteins composed of about 250 amino acids or less

often have a simple, compact globular shape.• Larger globular proteins are typically made up of two

or more recognizable and distinct structures, termed domains or modules – compact, folded protein structures that are usually stable by themselves in aqueous solution.

• Domains may consist of a single continuous portion of the protein sequence (see Figure 6.23).

• In some proteins, the domain sequence is interrupted by a sequence belonging to another part of the protein (Figure 6.24).

Most domains consist of a single continuous portion of the protein sequence

Figure 6.23 Ton-EBP is a DNA-binding protein consisting of two distinct domains.

A large domain of two sequences connected by the sequence of another domain

Figure 6.24 Malonyl CoA:ACP transacylase is a metabolic enzyme consisting of two domains. The large (blue) domain includes residues 1-132 and 198-316. The small (gold) domain consists of residues 133-197.

Many proteins are composed of several distinct domains• Multidomain proteins typically possess the sum of

functional properties and behaviors of their constituent domains.

• Proteins consisting of multiple domains probably evolved by the fusion of genes that once coded for separate proteins.

• About 90% of domains in proteins have been duplicated in other proteins.

• Many proteins even contain multiple copies of the same domain.

• Some of these often-duplicated domains are shown in Figure 6.25.

Many proteins are composed of several distinct domains

Figure 6.25 Several protein domains found in the construction of complex multimodule proteins.

Classification Schemes for the Protein Universe Are Based on Domains• Several comprehensive projects have organized the

available information on protein domains into defined hierarchies or levels of protein structure.

• The Structural Classification of Proteins (SCOP) database recognizes five overarching classes.

• SCOP is based on levels that embody the evolutionary and structural relationships among known proteins.

• CATH (standing for Class, Architecture, Topology, Homologous superfamily) is another system.

• CATH differs from SCOP in combining manual analysis with quantitative algorithmic analysis.

Classification Schemes for the Protein Universe Are Based on Domains

• Common features of SCOP and CATH:• Class is determined from overall composition of

secondary structure elements in a domain.• Fold describes the number, arrangement, and

connections of these secondary structure elements.

• Superfamily includes domains of similar folds and usually similar functions.

• Family usually includes domains with closely related amino acid sequences.

Classification Schemes for the Protein Universe Are Based on Domains

Figure 6.27 SCOP and CATH are hierarchical classification systems for the known proteins. Proteins are classified in SCOP by a manual process, whereas CATH combines manual and automated procedures. Numbers indicate the population of each category.

Structure and Function are Not Always Linked

• Because structure depends on sequence, and because function depends on structure, it is tempting to imagine that all proteins of similar structure should share a common function, but this is not always true.

• Some proteins of similar domain structure have different functions.

• Some proteins of similar function possess very different structures.

• See examples in Figure 6.28.

Structure and Function are Not Always Linked

Figure 6.28 (a) Some proteins share similar structural features but carry out different functions.(b) Proteins with different structures can carry out similar functions.

Denaturation Leads to Loss of Protein Structure and Function• The cellular environment is suited to maintaining the

weak forces that preserve protein structure and function.

• External stresses can disrupt these forces in a process termed denaturation – the loss of structure and function. (Heat, extremes of pH, detergents, 10 M urea, 6 M guanidine HCl, mechanical agitation, precipitating agents).

• The cooking of an egg is an everyday example.• Ovalbumin, the principal protein in egg white,

remains in its native structure up to a characteristic melting temperature, Tm. Above this temperature, the structure unfolds and function is lost.

Denaturation Leads to Loss of Protein Structure and Function

Figure 6.29 The proteins of egg white are denatured during cooking. More than half of the protein in egg white is ovalbumin.


Protein 6.30 Proteins can be denatured by heat, with commensurate loss of function.


Figure 6.31 Proteins can be denatured (unfolded) by high concentrations of guanidine-HCl or urea. The denaturation of chymotrypsin is plotted here.

Anfinsen’s Classic Experiment Proved that Sequence Determines Structure

Figure 6.32 Ribonuclease can be unfolded by treatment with urea, and β-mercaptoethanol (MCE) which cleaves disulfide bonds. Anfinsen showed that ribonuclease structure (and function) could be restored under appropriate conditions.

Is There a Single Mechanism for Protein Folding?

• How a protein achieves its stable, folded state is a complex question.

• Levinthal’s paradox demonstrates that proteins cannot fold by sampling all possible conformations.

• So, there must be a favored or guided route.• What factors play a role in the protein folding

processes as the protein leaves the ribosome ?• The hydrophobic effect (entropy): Low ΔG• Molecular chaperones: Guidance• Protein disulfide isomerase: Correct –S-S-

• Prolyl cis-trans isomerase: Pro structure

Postulated Themes of Protein Folding

• Secondary structures – helices, sheets, and turns – probably form first and provide stability (H-Bonding).

• Nonpolar residues may aggregate or coalesce in a process termed a hydrophobic collapse.

• Subsequent steps probably involve formation of long-range interactions between secondary structures or involving other hydrophobic interactions.

• The folding process may involve one or more intermediate states, including transition states and what have become known as molten globules.

Folding of Globular Proteins

• Small initial elements of structure enhance subsequent folding (cooperativity).

• Peptide chain must satisfy the constraints inherent in its own structure (aa sequence).

• Peptide chain must fold so as to "bury" the hydrophobic side chains, minimizing their contact with water.

• Peptide chains, composed of L-amino acids, have a tendency to undergo a "right-handed twist ".

Simulations of Protein Folding

Figure 6.33 Computer simulations of folding and unfolding of proteins can reveal possible folding pathways.

The Protein Folding Energy Landscape

Figure 6.34 A model for the steps involved in the folding of globular proteins.

Ken Dill has suggested that the folding process can be pictured as a funnel of free energies. The rim at the top represents the many unfolded states. Polypeptides fall down the wall of the funnel to lower energies as they fold.

What is the Thermodynamic Driving Force for Folding of Globular Proteins?

• Distinguish ΔH & TΔS for polar vs. nonpolar groups. The ΔH & TΔS cancel for polar groups.

• Separate the ΔH & TΔS terms for the peptide chain and the solvent.

• The largest favorable contribution to folding is the entropy term for the interaction of nonpolar residues with the solvent.

• A very important point – nonpolar residues force order on the solvent in the unfolded state. Folding buries the nonpolar residues inside the protein structure, producing a large entropy increase for the liberated solvent molecules.

Marginal Stability of the Tertiary Structure Makes Proteins Flexible

• A typical folded protein is only marginally stable.• It is logical to think that stability is important to

function, so why are proteins often only marginally stable ?

• The answer appears to lie in flexibility and motion.

• It is becoming increasingly clear that flexibility and motion are important to protein function.

Motion is Important for Globular Proteins

Figure 6.35 Proteins are dynamic structures. The marginal stability of a tertiary structure leads to flexibility and motion in the protein.


• Protein are dynamic structures – they oscillate and fluctuate continuously about their average or equilibrium structures.

• This flexibility is essential for protein functions, including:• Ligand binding• Enzyme catalysis• Enzyme regulation



Figure 6.36 The cis and trans configurations of proline residues in peptide chains are almost equally stable. Proline cis-trans isomerizations of the α-Cs with respect to the peptide bond, often occur over relatively long time scales, and can alter protein structure significantly.

The Folding Tendencies and Patterns of Globular Proteins

• Globular proteins adopt the most stable tertiary structures possible.

• To do this, the peptide chain must:• satisfy the constraints inherent in their structure.• fold so as to bury hydrophobic side chains.

• Polypeptide chains have a tendency to twist slightly in a right-handed direction.

• This tendency is manifested in the formation of right-handed twists in β-sheets and right-handed crossovers in parallel β-sheets.

The Folding Tendencies and Patterns of Globular Proteins

Figure 6.37 (a) The natural right-handed twist of polypeptide chains, and (b) the types of connections between β-strands.

Layer Structures in Globular Proteins

• The need to bury hydrophobic residues inside the protein, protecting them from solvent water, leads to formation of “layers” of structure in the protein.

• Globular proteins can be pictured as consisting of layers of backbone, with hydrophobic core regions between and on either side of them.

• More than half the known globular proteins have two layers of backbone, with one hydrophobic core.

• One-third of proteins are composed of three layers, with two hydrophobic cores.

• There are a few four layer structures and one five layer structure.

Layer Structures in Globular Proteins

Figure 6.38 Examples of protein domains with different numbers of layers of backbone structure. Hydrophobic residues (shown in yellow) are buried between the backbone layers.

Most Globular Proteins Belong to One of Four Structural Classes

• Proteins can be classified according to the type and arrangement of secondary structure.

• There are four classes:• All α proteins, in which α helices predominate.• All β proteins, in which β sheets predominate.• α/β proteins, in which helices and sheets are

intermingled.• α+β proteins, which contain separate α-helical

and β-sheet domains.


Figure 6.39 Four major classes of protein structure (as defined in the SCOP database).


Figure 6.39 Four major classes of protein structure (as defined in the SCOP database).

Molecular Chaperones Are Proteins That Help Other Proteins to Fold

• Why are molecular chaperones needed if the information for folding is inherent in the sequence ? • To prevent errors in folding and correct

those that do occur.• to protect nascent proteins from the

concentrated protein matrix in the cell and perhaps to accelerate slow steps.

• Chaperone proteins were first identified as "heat-shock proteins" (hsp60 and hsp70) which formed at elevated temperatures.

Intrinsically Unstructured Proteins

• Many proteins exist and function normally in a partially unfolded state.

• These intrinsically unstructured proteins (IUPs) do not possess uniform structural properties but are still essential for cellular function.

• These proteins are characterized by a nearly complete lack of structure and high intramolecular flexibility.

• IUPs do adopt well-defined structures in complexes with their target proteins.

• IUPs are characterized by an abundance of polar residues and a lack of hydrophobic residues.

Some Proteins Are Intrinsically Unstructured

Figure 6.40 Intrinsically unstructured proteins (IUPs) contact their target proteins over a large surface area.

Some Proteins Are Intrinsically Unstructured

Figure 6.40 Intrinsically unstructured proteins (IUPs) contact their target proteins over a large surface area.

6.5 How Do Protein Subunits Interact at the Quaternary Level of Structure?

What are the forces driving quaternary association?

• Typical Kd for two subunits: 10-8 to 10-16M!

• These values correspond to energies of 50-100 kJ/mol at 37 C

• Entropy loss due to association - unfavorable • Entropy gain due to burying of hydrophobic groups

- very favorable!


Figure 6.41 The quaternary structure of liver alcohol dehydrogenase.


The subunit compositions of several proteins. Proteins with two or four subunits predominate in nature, and many cases of higher numbers exist.


Figure 6.42 Isologous and heterologous associations between protein subunits.


Figure 6.43 Many proteins form tetramers by means of two sets of isologous interactions. The tetramer of transthyretin is formed by isologous interactions between the large β-sheets of two transthyretin dimers.


Figure 6.44 Multimeric proteins are symmetric arrangements of asymmetric objects. A variety of symmetries is displayed in these multimeric structures.


Figure 6.45 Schematic drawing of an immunoglobulin molecule, showing the intermolecular and intramolecular disulfide bonds.

Open 4o Structures Can Polymerize

Figure 6.46 The structure of a typical microtubule, showing the arrangement of the α- and β-monomers of the tubulin dimer.

What are the structural and functional advantages driving 4o association?

Benefits of 4o Structure

• Stability: reduction of surface to volume ratio improves solvent interaction

• Genetic economy and efficiency: less DNA is required to make a monomeric subunit

• Bringing catalytic sites together: can facilitate enzyme activity

• Cooperativity: interaction between subunits facilitates function and regulation

End Chapter 6Proteins: Secondary, Tertiary, and

Quaternary Structure

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Chapter 6 Proteins: Secondary, Tertiary, and Quaternary Structure

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