4 | The Three-

Dimensional Structure
of Proteins
© 2017 W. H. Freeman and Company
 CHAPTER 4
The Three-Dimensional Structure of Proteins
Learning goals: six themes
• The three-dimensional structure taken up by a protein are determined by its
amino acid sequence.
• The function of a typical protein depends on its structure.
• Most isolated proteins exist in one or a small number of stable structural forms.
• The most important forces stabilizing the specific structures maintained by a
given protein are noncovalent; the hydrophobic effect is particularly important.
• Some common structural patterns that help to organize our understanding of
protein architecture.
• Protein structures are not static. All proteins undergo changes in conformation
ranging from subtle to dramatic. Parts of many proteins have no discernible
structure (→ critical to their function).
 Overview of Protein Structure

• Unlike most organic polymers, protein molecules adopt a specific three-

dimensional conformation (spatial arrangement of atoms in a protein).
• For the vast majority of proteins, a particular structure or small set of
structures is critical to function.
• Proteins in any of their functional, folded conformations are called
native proteins.
• The conformations existing under a given set of conditions are usually
the ones that are thermodynamically the most stable.
• What principles determine the most stable conformations of a typical
protein?
 A Protein’s Conformation Is Stabilized
Largely by Weak Interactions
• Hydrophobic effect
– The hydrophobic effect is clearly important in stabilizing conformation.
– Hydrophobic amino acid side chains (especially Leu, Ile, Val, Phe, and Trp) are
positioned so that they are clustered in a protein’s interior, away from water, when the
protein is folded, forming a hydrophobic protein core.
• Hydrogen bonds
– Interaction of N−H and C=O of the peptide bond leads to local regular structures such
as  helices and  sheets.
• Van der Waals interactions
– weak and, individually, contribute little to overall protein stability.
– However, in a well-packed protein, or in an interaction between a protein and another
protein, the number of such interactions can be substantial.
• Electrostatic (ionic) interactions
– Salt bridges (bonds between oppositely charged residues) strongly stabilize the protein.
• Most of the structural patterns reflect two simple rules:
– hydrophobic residues are largely buried in the protein interior
– The number of hydrogen bonds and ionic interactions within the protein is maximized.
Four Levels of Protein Structure
 Primary Structure: The Peptide Bond
• In the late 1930s, Linus Pauling and Robert
Corey embarked on a series of studies that laid
the foundation for our current understanding
of protein structure.
• Each peptide bond has some double-
bond character due to resonance.
• to exhibit a large dipole moment in the
favored trans configuration.
Linus Pauling (1901~1994)
• Nobel Prize in Chemistry in 1954
• Nobel Peace Prize in 1962
• one of the founders of the fields
of quantum chemistry and
molecular biology
• The theory of the chemical bond
• The structures of biological
molecules (protein secondary
structure), X-ray crystallography,
molecular model building
– Inspired the DNA structure
 The Peptide Bond Is Rigid and Planar
• Rotation around the peptide bond is not permitted due to resonance structure.
• The N—Cα and Cα—C bonds can rotate to define the dihedral angles ϕ and ψ.
– f (phi): angle around the  carbon—amide nitrogen bond
– y (psi): angle around the  carbon—carbonyl carbon bond
• The backbone of a polypeptide chain can thus be pictured as a series of rigid
planes.

• The organization around the peptide bond, paired with the identity of the R
groups, determines the secondary structure of the protein.
 Distribution of f and y Dihedral Angles
• The Ramachandran plot is a visual description of the combinations of ϕ and
ψ dihedral angles that are permitted in a peptide backbone and those that
are not permitted due to steric constraints.
• shows the common secondary structure elements
no steric overlap
• reveals regions with unusual backbone structure conformations that are
not allowed
• Some f and y combinations are very
unfavorable because of steric interference
of backbone atoms with other atoms in
the backbone or side chains.
• Some f and y combinations are more
favorable because of chance to form
favorable H-bonding interactions along
the backbone.

Ramachandran plot for L-Ala residues

 Protein Secondary Structure
• Secondary structure refers to any chosen segment of a polypeptide chain
and describes a local spatial arrangement of the polypeptide backbone.
• A regular secondary structure occurs when each dihedral angle, ϕ and ψ,
remains the same or nearly the same throughout the segment.
• It is unchanging and highly specific to the structure and function of that
particular protein.
• the  helix
– stabilized by hydrogen bonds between nearby residues
• the  sheet
– stabilized by hydrogen bonds between adjacent segments that
may not be nearby
• Where a regular pattern is not found, the secondary structure is
sometimes referred to as undefined or as a random coil (irregular
arrangement of the polypeptide chain).
 Idealized f and y Angles for Common Secondary
TABLE 4.1
Structures in Proteins

Structure f y
 Helix –57˚ –47˚

 Conformation

Antiparallel –139˚ +135˚

Parallel –119˚ +113˚

Collagen triple helix –51˚ +153˚

 Turn type I

i + 1a –60˚ –30˚

i + 2a –90˚ 0˚

 Turn type II

i+1 –60˚ +120˚

i+2 +80˚ 0˚
 The  Helix
• Helical backbone is held together by hydrogen
bonds between the backbone amides of an n n
(C=O) and n + 4 (N—H) amino acids.
• It is a right-handed helix with 3.6 residues (5.4 n+4
Å) per turn.
• Peptide bonds are aligned roughly parallel
with the helical axis.
• Side chains point out and are roughly
perpendicular with the helical axis.

Hydrophobic
residues
Amino Acid Sequence Affects Stability of the α Helix

• Not all polypeptide sequences adopt -helical structures.

• Each amino acid residue in a polypeptide has an intrinsic propensity to form an
α helix.
• Five types of constraints affect the stability of an α helix.
(1) the intrinsic propensity of an amino acid residue to form an α helix
(2) The interactions between R groups, particularly those spaced 3 (or 4) residues apart
(3) the bulkiness of adjacent R groups
(4) the occurrence of Pro and Gly residues
(5) interactions between amino acid residues at the ends of the helical segment and the
electric dipole inherent to the α helix
• Small hydrophobic residues such as Ala and Leu are strong helix formers.
• The tendency of a given segment of a polypeptide chain to form an α helix
therefore depends on the identity and sequence of amino acid residues within
the segment.
 Propensity of Amino Acid Residues to Take Up an α-Helical
TABLE 4-2
Conformation
Amino acid ΔΔG° (kJ/mol)a Amino acid ΔΔG° (kJ/mol)a

Ala 0 Leu 0.79

Arg 0.3 Lys 0.63

Asn 3 Met 0.88

Cys 3 Pro >4

Gln 1.3 Ser 2.2

Glu 1.4 Thr 2.4

Gly 4.6 Tyr 2.0

His 2.6 Trp 2.0

Ile 1.4 Val 2.1

Sources: Data (except proline) from J. W. Bryson et al., Science 270:935, 1995. Proline data from J. K.
Myers et al., Biochemistry 36:10,923, 1997.
aDDG° is the difference in free-energy change, relative to that for alanine, required for the amino acid

residue to take up the α-helical conformation. Larger numbers reflect greater difficulty taking up the α-
helical structure. Data are a composite derived from multiple experiments and experimental systems.
 The Helix Dipole
• Recall that the peptide bond has a strong dipole
moment.
– C−O (carbonyl) negative
– N−H (amide) positive
• All peptide bonds in the  helix have a similar
orientation.
• The  helix has a large macroscopic dipole moment
that is enhanced by unpaired amides and carbonyls
near the ends of the helix.
• Negatively charged residues often occur near the
positive end of the helix dipole.
 The β Conformation Organizes Polypeptide
Chains into Sheets
• Pauling and Corey predicted a second type of repetitive structure, a more
extended conformation of polypeptide chains, the β conformation.
• The arrangement of several segments (zigzag structure) side by side, all of
which are in the β conformation, is called a β sheet.
• The planarity of the peptide bond and tetrahedral geometry of the  carbon
create a pleated sheet-like structure.
• Sheet-like structure are held together by hydrogen bonds between the amide
and carbonyl groups of the peptide backbone in different strands.
• The R groups protrude from the zigzag structure, alternating in an up-and-
down direction.
 Parallel and Antiparallel  Sheets
• Two major orientations of  sheets are determined by the directionality of
the strands.
• In parallel  sheets, the H-bonded strands are oriented in the same direction.
• Hydrogen bonds between strands are bent (weaker).
• In antiparallel  sheets, the H-bonded strands are oriented in opposite
directions.
• Hydrogen bonds between strands are linear (stronger).
 β Turns Are Common in Proteins
•  turns occur frequently whenever strands in  sheets change the direction.
• The structure is a 180° turn involving four amino acid residues.
• The turn is stabilized by a hydrogen bond from a carbonyl oxygen (1st residue)
to amide Hydrogen (4th residue) of the bends.
• Proline (cis configuration) in position 2 or glycine (small and flexible) in
position 3 are common in  turns.

For peptide bonds involving the

imino nitrogen of proline, about
6% are in the cis configuration;
many of these occur at β turns.
 Common Secondary Structures Have
Characteristic Dihedral Angles
• The α helix and the  conformation are the major repetitive secondary
structures in a wide variety of proteins.
• Every type of secondary structure can be completely described by the
dihedral angles ϕ and ψ associated with each residue.
• As shown by a Ramachandran plot, the dihedral angles that define the α
helix and the β conformation fall within a relatively restricted range of
sterically allowed structures.

The values of ϕ and ψ for all

the amino acid residues except
Gly in the enzyme pyruvate
kinase
 Determination of Secondary Structure:
Circular Dichroism (CD) Analysis
• Any form of structural asymmetry in a molecule gives rise to differences in
absorption of left-handed versus right-handed circularly polarized light.
• This difference can be measured by circular dichroism (CD) spectroscopy.
• For proteins, spectra are obtained in the far UV region (190 to 250 nm); a signal
is obtained when the peptide bond (chromophore) is in a folded environment.
• CD measures the difference in molar extinction coefficients (D) for left- and
right-handed, circularly polarized light.
• The α-helix and β conformations have
characteristic CD spectra.
• CD spectra can determine whether proteins
are properly folded, estimate the fraction
of the protein that is folded in either of the
common secondary structures, and
monitor transitions between the folded and
unfolded states.
 Protein Tertiary Structure
• Tertiary structure refers to the overall spatial (three-dimensional)
arrangement of all atoms in a protein.
• Stabilized by numerous weak interactions between amino acid side
chains
− largely hydrophobic and polar interactions
− can be stabilized by disulfide bonds
• Interacting amino acids are not necessarily next to each other in the
primary sequence.
• Two major classes:
– Fibrous proteins, with polypeptide chains arranged in long strands or
sheets
– Globular proteins, with polypeptide chains folded into a spherical or
globular shape
 Fibrous Proteins:
From Structure to Function
• Fibrous proteins share properties that give strength and/or flexibility to the
structures.
• The fundamental structural unit is a simple repeating element of secondary
structure.
• All fibrous proteins are insoluble in water, a property conferred by a high
concentration of hydrophobic amino acid residues both in the interior of the
protein and on its surface.
• Many similar polypeptide chains are packed together to form elaborate
supramolecular complexes.
TABLE 4-3 Secondary Structures and Properties of Some Fibrous Proteins

Structure Characteristics Examples of occurrence

α Helix, cross-linked by Tough, insoluble protective structures α-Keratin of hair, feathers, nails
disulfide bonds of varying hardness and flexibility
β Conformation Soft, flexible filaments Silk fibroin
Collagen triple helix High tensile strength, without stretch Collagen of tendons, bone matrix
 Structure of -Keratin in Hair

• Hair α-keratin is an elongated α helix.

• Pairs of these helices are interwound in a left-handed sense to form two-chain
coiled coils.
• These then combine in higher-order structures called protofilaments and
protofibrils.
• About four protofibrils combine to form an intermediate filament.
 cool • revert to α-helix
Heat conformation

• New disulfide bonds form

• Breaking disulfide & hydrogen bonds
• α-helical structures uncoil

• When hair is exposed to moist heat, it can be stretched. At the molecular level,
the α helices in the α-keratin of hair are stretched out until they arrive at the
fully extended β conformation.
• On cooling, they spontaneously revert to the α-helix conformation. The
characteristic “stretchability” of α-keratins, as well as their numerous disulfide
crosslinkages, is the basis of permanent waving (or hair straightening).
 Structure of Collagen
• Collagen is an important constituent of connective tissue: tendons, cartilage,
bones, cornea of the eye.
• The collagen helix is a unique secondary structure, quite distinct from the α
helix (left-handed and three amino acid residues per turn; called α chains).
• Collagen is a coiled coil with distinct tertiary and quaternary structures:
– Three collagen chains are supertwisted about each other to a right-handed
superhelical triple helix.

• A typical mammal has more than 30

structural variants of collagen, particular to
certain tissues and each somewhat different
in sequence and function.
• Many triple-helices assemble into a collagen
fibril.
Collagen Fibrils
• Collagen superstructures are formed
by cross-linking of collagen triple-
helices to form collagen fibrils.
• Crosslinks are covalent bonds
between Lys or HyLys, or His amino
acid residues.
 Silk Fibroin
• Silk Fibroin, the protein of silk, is produced by insects and spiders.
• Antiparallel  sheet structure
• Small side chains (Ala and Gly) allow the close packing of sheets.
• Structure is stabilized by hydrogen bonding within sheets and the
optimization of van der Waals interactions between sheets.
 Structural Diversity Reflects Functional
Diversity in Globular Proteins
• Globular protein structures are compact and varied.
• Myoglobin
• a relatively small (Mr 16,700),
oxygen-binding protein of muscle cells.
• functions both to store oxygen and to
facilitate oxygen diffusion in rapidly
contracting muscle tissue.
• a single polypeptide chain of 153 amino acid residues
• a single iron protoporphyrin, or heme, group The Heme group
(myoglobin, hemoglobin,
cytochromes, and etc)

His

hydrophobic residues Leu, Ile, Val, and Phe

 Globular Proteins Have a Variety of
Tertiary Structures
• Each of globular proteins has a distinct structure, adapted for its particular
biological function.
– Each is folded compactly.
– Hydrophobic amino acid side chains are oriented toward the interior
– Hydrophilic side chains are on the surface.
– The structures are also stabilized by a multitude of hydrogen bonds and some
ionic interactions.
• The three-dimensional structure of a typical globular protein can be
considered an assemblage of polypeptide segments in the α-helix and β
conformations, linked by connecting segments.
• The structure can then be defined by how these segments stack on one
another and how the segments that connect them are arranged.
• To understand a complete three-dimensional structure, we need to analyze
its folding patterns.
• Globular proteins are composed of different motifs folded together.
 Approximate Proportion of α Helix and β Conformation in
TABLE 4-4
Some Single-Chain Proteins

Residues (%)a
Protein (total residues) α Helix β Conformation
Chymotrypsin (247) 14 45
Ribonuclease (124) 26 35
Carboxypeptidase (307) 38 17
Cytochrome c (104) 39 0
Lysozyme (129) 40 12
Myoglobin (153) 78 0
SOURCE: Data from C. R. Cantor and P. R. Schimmel, Biophysical Chemistry, Part I: The
Conformation of Biological Macromolecules, p. 100, W. H. Freeman and Company, 1980.
aPortions of the polypeptide chains not accounted for by α helix or β conformation consist of bends and
irregularly coiled or extended stretches. Segments of α helix and β conformation sometimes deviate
slightly from their normal dimensions and geometry.
• The number of known three-dimensional protein structures is now
more than 100,000 and doubles every couple of years.
• Protein Data Bank (PDB; www.pdb.org).
• The PDB is an archive of experimentally determined three-dimensional
structures of biological macromolecules, containing virtually all of the
macromolecular structures (proteins, RNAs, DNAs, etc.).
– The data files in the PDB describe the spatial coordinates of each atom for
which the position has been determined (many of the cataloged structures
are not complete).
– Additional data files provide information on how the structure was
determined and its accuracy (using structure visualization software).
 Motif (fold)
• A motif or fold is a recognizable folding pattern involving two or more
elements of secondary structure and the connection(s) between them.
– The terms “motif” and “fold” are often used interchangeably, although “fold” is
applied more commonly to somewhat more complex folding patterns.
– Also called a (more rarely) supersecondary structure.
– A motif is not a hierarchical structural element falling between secondary and
tertiary structure. It is simply a folding pattern.
• Motifs can be found as recurring structures in numerous proteins.
• Globular proteins are composed of different motifs folded together.

Simple motif

More elaborate motif

 Domain
• A domain is a part of a polypeptide chain that is independently stable or could
undergo movements as a single entity with respect to the entire protein.
• Polypeptides with more than a few hundred amino acid residues often fold
into two or more domains.
• In a protein with multiple domains, each domain may appear as a distinct
globular lobe.
• Different domains often have distinct functions, such as the binding of small
molecules or interaction with other proteins.
•

Calcium-binding domains

Structural domains in the polypeptide troponin C

 Repeated Motifs Contribute to Final Fold
Stable folding patterns in proteins

• The α/β barrel is a commonly occurring

motif constructed from repetitions of
the β-α-β loop motif.
 Intrinsically Disordered Proteins
• Contain protein segments that lack definable 3-D structure.
• Lack a hydrophobic core.
• Characterized by high densities of charged amino acid residues
– Lys, Arg, Glu, and Pro
• As many as a third of all human proteins may be unstructured or have
significant unstructured segments.

• The lack of an ordered structure

can facilitate a kind of functional
promiscuity, allowing one protein
to interact with multiple partners.
• Some intrinsically disordered
proteins act to inhibit the action
of other proteins by an unusual
mechanism.

A score of 1.0: probability of 100% that a protein will be disordered.

 Protein family & superfamily
• Among > 80,000 distinct protein structures archived in the PDB, only about
1,200 different folds or motifs are represented.
• Protein tertiary structure is more reliably conserved than amino acid sequence.
• Protein family: proteins with significant similarity in primary structure and/or
with similar tertiary structure and function
– Closely related proteins with a clear evidence for their evolutionary origin
– 4,000 different protein families in the PDB
• Superfamily: two or more families that have little similarity in amino acid
sequence but make use of the same major structural motif and have functional
similarities
• A protein family may be widespread in all three domains of cellular life, the
Bacteria, Archaea, and Eukarya, suggesting an ancient origin.
• Structural Classifications Of Proteins (SCOP2) database
– http://scop2.mrc-lmb.cam.ac.uk
– SCOP2 database is curated manually, with the objective of placing proteins in the
correct evolutionary framework based on conserved structural features.
– All of the protein information can be searched within 4 different categories: (1)
protein relationships, (2) structural classes, (3) protein types, and (4) evolutionary
events.
Organization of proteins based on motifs

• Evolutionary relationships conserve structure

as well as function.
• Topology diagrams provide a way to visualize
elements of secondary structure and their
interconnections in two dimensions.
• The SCOP2 database organizes protein folds
into four classes: all α, all β, α/β, and α + β.

PDB ID

Topology diagram
 Quaternary Structure
• A quaternary structure is formed by the assembly of individual polypeptides
into a larger functional cluster.
• A multisubunit protein is also referred to as a multimer.
• The repeating structural unit in such a multimeric protein, whether a single
subunit or a group of subunits, is called a protomer.

Quaternary structure of deoxyhemoglobin

α subunits

β subunits

A tetramer or
a dimer of α β protomers
X-Ray Crystallography (Diffraction)

Steps
• purify the protein
• crystallize the protein
• collect x-ray diffraction data
• calculate electron density
• fit known amino acid residues into density
Pros
• no size limits
• well established
Cons
• limited to molecules that can be crystallized
• difficult for membrane proteins
• cannot resolve (see) hydrogens
Nuclear Magnetic Resonance

Steps
• purify the protein
• dissolve the protein
• collect NMR data
• assign NMR signals
• calculate the structure
Pros
• no need to crystallize the protein
• can be carried out on
macromolecules in solution
• can see many hydrogens
• can also illuminate the dynamic
side of protein structure
Cons
• difficult for insoluble proteins
• works best with small proteins
Proteostasis: Synthesis, Assembly, and Degradation
of Proteins in vivo

• The continual maintenance of the

active set of cellular proteins required
under a given set of conditions
(=proteostasis) is accomplished by the
coordination of many different
pathways.
– protein synthesis and folding
– the refolding of proteins that are
partially unfolded
– the sequestration and degradation of
proteins that have been irreversibly
unfolded or are no longer needed

the natural, regulated mechanism of the cell that

removes unnecessary or disfunctional components.
Loss of Protein Structure Results in Loss of Function
• A loss of three-dimensional structure sufficient to cause loss of function is
called denaturation.
• Proteins can be denatured by:
• heat or cold, pH extremes, organic solvents, chaotropic agents or detergent (urea
and guanidinium hydrochloride)
• An abrupt loss of structure (and function) occurs over a narrow temperature
range: unfolding is a cooperative process.
• Denaturation often leads to protein precipitation, a consequence of protein
aggregate formation as exposed hydrophobic surfaces associate.

Denaturation was monitored by circular dichroism.

Amino Acid Sequence Determines Tertiary Structure

• Denaturation of some proteins is reversible.

• Certain globular denatured proteins regain
their native structure and their biological
activity if returned to conditions in which the
native conformation is stable. This process is
called renaturation.
• Ribonuclease Refolding Experiment
(denaturation and renaturation)
• The experiment earned Chris Anfinsen the
1972 Chemistry Nobel Prize.
 Polypeptides Fold Rapidly by a Stepwise Process
• In living cells, proteins are assembled from amino
acids at a very high rate.
– In E. coli cells, about 5 seconds for a complete,
biologically active protein molecule (100 AA) at 37 C.
• However, the synthesis is not enough; the protein
must fold.
• Protein folding is not a completely random, trial-
and-error process. There must be shortcuts.
• The major folding pathways are hierarchical.
– Local secondary structures form first. Certain amino
acid sequences fold readily into α helices or β sheets.
– Assembly of local structures is followed by longer-range interactions between, say, two
elements of secondary structure that come together to form stable folded structures.
– The hydrophobic effect plays a significant role throughout the process, as the
aggregation of nonpolar amino acid side chains provides an entropic stabilization to
intermediates and, eventually, to the final folded structure.
– The process continues until complete domains form and the entire polypeptide is
folded.
 How Can Proteins Fold So Fast?
• Proteins fold to the lowest-energy fold in the microsecond to second time scales.
• It is mathematically impossible for protein folding to occur by randomly trying
every conformation until the lowest-energy one is found (Levinthal’s paradox).
– 10100 different conformations for a 100 AA polypeptide → 1077 years
• Search for the minimum is not random because the direction toward the native
structure is thermodynamically most favorable.
• The folding process can be viewed as a kind of free energy funnel.
– The funnels can have a variety of shapes, depending on the number and types of
folding intermediates in the folding pathways.
folding intermediates
Multiple possible only one folding of substantial stability
Multiple pathways on virtually every
stable intermediates pathway leading to
leading to one
leading to the native one stable native pathway leading to the
stable structure native state
structure structure

ΔG represented by the depth of

the funnel & the native structure
(N) (lowest free-energy point)
 Chaperones Prevent Misfolding and
Aggregation of Unfolded Peptides
• Not all proteins fold spontaneously.
• Folding for many proteins requires chaperones,
proteins that interact with partially folded or
improperly folded polypeptides, facilitating
correct folding pathways or providing
microenvironments in which folding can occur.
• Two major families of chaperones
• Hsp70 family (heat shock proteins of Mr
70,000)
– bind to regions of unfolded polypeptides that
are rich in hydrophobic residues.
– “protect” both proteins subject to denaturation
by heat and new peptide molecules being
synthesized (and not yet folded).
• Chaperonins: elaborate protein complexes required for the folding of some
cellular proteins that do not fold spontaneously.
– In E. coli, 10% to 15% of cellular proteins require the resident chaperonin system
(GroEL/GroES).
 Chaperonins Facilitate Folding

E. coli chaperonins GroEL

(a member of the Hsp60
protein family) and GroES

GroEL/GroES complex
Protein Misfolding Is the Basis of Numerous Human
Genetic Disorders
• Protein misfolding is a substantial problem in all
cells, and a quarter or more of all polypeptides
synthesized may be destroyed because they do
not fold correctly.
• Misfolding causes or contributes to the
development of serious disease.
• Type 2 diabetes, Alzheimer disease, Huntington
disease, and Parkinson disease, are associated
with misfolding.
• a soluble protein that is normally secreted from
the cell is secreted in a misfolded state and
converted into an insoluble extracellular amyloid
fiber with a high degree of β-sheet structure
(characteristic of Alzheimer disease).
• Misfolded  amyloid promotes aggregation at
newly exposed protein-protein interface.
• Correctly folded helices are lost and peptides
form  strands,  helices, and  sheets.
• A misfolded brain protein seems to be the causative agent of several rare
degenerative brain diseases in mammals.
– BSE (bovine spongiform encephalopathy (holes in brain); also known as mad cow
disease)
– Kuru, Creutzfeldt-Jakob disease in human
– scrapie in sheep
• Disease-causing agents seemed to lack nucleic acids and was a protein.
• The infectious agent has been traced to a single protein (Mr 28,000), called prion
protein (PrP). (proteinaceous infectious → proin → prion)
• Prion protein is a normal constituent of brain tissue in all mammals.
• Illness occurs only when the normal cellular PrP, or PrPC, occurs in an altered
conformation called PrPSc (Sc denotes scrapie).
– The structure of PrPC has two α helices but PrPSc is very different, with much of the
structure converted to amyloidlike β sheets.
– The interaction of PrPSc with PrPC converts the latter to PrPSc, initiating a domino effect.
– The mechanism is not understood. And how prion protein affects brain function?
– Prionlike proteins may be responsible for additional neurodegenerative diseases
(Parkinson disease).