Fibrous proteins

2. COLLAGEN and ELASTIN are examples of well
characterized fibrous proteins that serve structural
functions in the body.
Each fibrous protein exbits special mechanical
properties,resulting from its unique structure,which
are obtained by combing specific amino acids into
regular,secondary structural elements.

3. COLLAGEN
COLLAGEN is the most abundant protein in the
human body.
A typical collagen molecule is a long, rigid structure
in which three polypeptides(referred to as α-chains)
are wound around one another in a rope like triple
helix.

4. Types of Collagen
The collagen superfamily of proteins include more
than twenty collagen types,as well as additional
proteins that have collagen like properties.
The three polypeptide chains are held together by
hydrogen bonds between the chains.
Variations in the aminoacid sequence of the α chains
result in structural components that are about the
same size(approximately 100 aminoacids long),but
with slightly different properties.

5. The α chains are combined to form various types of
collagen found in the tissues.
For example Type 1 collagen contains two α1 chains
and one α2 chain (α1 ₂ α2 ).
Type 2 collagen contains three α1(α1 ₃) chain.
The collagens can be organized into three groups
depending upon their location and functions in the
body.

7. Structure of collagen
Amino acid
sequence
1.Rich in proline and
glycine.
2. –Gly-X-Y-
3.X is frequently
PROLINE and Y is
Hydroxyproline or
hydroxy lysine

8. Triple helical
structure
Hydroxy proline
and Hydroxy
lysine

9. Glycosylation.
The hydroxyl group of hydroxylysine residues of
collagen may be enzymatically glycosylated.Most
commonly glucose and galactose are sequentially
attached to the polypeptide chain prior to triple helix
formation.

10. BIOSYNTHESIS OF COLLAGEN
The polypeptide precursors of collagen molecule are
formed in the fibroblasts(or in the related osteoblasts
of bone and chondroblasts of cartilage),and are
secreated into the extracellular matrix.After
enzymatic modification,mature collagen monomers
aggregate and become crosslinked to form collagen
fibrils.

11. 1.Formation of pro-α-chains.
2.Hydroxylation
3.Glycosylation
4.Assembly and secretion
5.Extracellular cleavage of procollagen molecules.
6.Formation of collagen fibrils.
7.Cross linked formation

15. DEGRADATION OF COLLAGEN
Normal collagens are highly soluble
molecules,having half lives as long as several
months.However the connective tissue is dynamic
and is constantly being remodeled,often in response
to the growth or injury of the tissue.Breakdown of
collagen is done by:
COLLAGENASES
MATRIX PROTEINASES

16. Collagen diseases
More than 100 mutations have been identified in 22
genes coding for twelve of the collagen types.
1.Ehlers-Danlos syndrome(EDS)
Hetrogeneous group of connective tissue disorders
that result from inheritable defects in the metabolism
of fibrillar collagen molecules.

17. EDS can result from collagen processing enzymes (lysyl-
hydroxylase deficiency or procollagen peptidase
deficiency).
Mutations in the amino acid sequences of collagen types
I.III,Or V.
The most clinically important mutations are found in the
gene for type III collagen.
Collagen containing mutant chains is not secreated,and is
either degraded or accumulated to high levels in
intracellular compartments.
Mutations in type 1 collagen fibrils results in stretchy skin
and loose joints

19. 2.Osteogenesis imperfecta (OI)
Also known as brittle bone syndrome.
Retarted wound healing and a rotated and twisted
spine leading to a “humped-back” appearances are
common features of the disease.

20. Type 1 OI,Osteogenesis imperfect tarda.
Presents in early infancy with fractures secondary to
minor trauma,and may be suspected if prenatal ultrasound
detects bowing or fractures of lonf bones.
Type 2 OI,Osteogenesis imperfecta congenita
More severe.
Patients die in utero.
Mutations in the αChains of type 1 collagen.
Subsitution of glycine with aminoacids containing bulky
side chains which hinder in the formation of triple helix of
collagen.

21. ELASTIN
Connective tissue protein with rubber like properties.
Elastic fibers composed of elastin and glycoprotein
microfibrils are found in lungs.the walls of large
arteries,and elastic ligaments.
They can be stretched to several times their normal
length but recoil to their original shape when the
stretching force is relaxed.

22. Structure of elastin
Elastin is insoluble protein polymer.
Synthesized from precursor,tropoelastin,which is a
linear polypeptide composed of 700 a.as.,that are
primarily small and non polar.
Elastin is also rich in proline and lysine,but contains
only a little hydroxyproline and NO
hydroxylysine.

23. Tropoelastin secreted by the cell into the
extracellular space interacts with the specific
gycoprotein microfibrils,such as fibrilin.
Mutations in the fibrilin gene are responsible for
MARFAN’S SYNDROME .

24. Some of the LYSYL Side chains of the tropoelastin
polypeptides are oxidatively deaminated by lysyl
oxidase,forming ALLYSINE
residues.
Three of the allysyl side chains plus one
unaltered lysyl side chain from the same or
neighbouring polypeptides form a DESMOSINE cross
link

26. ROLE OF α₁-ANTITRYPSIN IN
ELASTIN DEGRADATION
α₁ ANTITRYPSIN.
Plasma protein
Has impportant physiological role of inhibiting
neutrophil elastase.
Role of α₁ antitrypsin in the lungs .

28. Emphysema resulting from α₁ ANTITRYPSIN
deficiency.
A number of different mutations in the α₁ antitrypsin
gene are known to cause a deficiency of this
protein,but one single purine base mutation(GAG-
AAG),resulting in the substitution of lysine for
glutamic acid at position 342 is clinically the most
widespread.

29. A specific methionine in α₁-antitrypsin is required for
the binding of the ihibitor to its target proteases.
Smoking causes the oxidation and sebsequent
inactivation of methinine residue,thereby rendering
the inhibitor powerless to neutralize elastase.

31. Primary structure
 The sequence,type and number of aminoacids in a
protein is called the primary structure of protein.
Understanding the primary structure of protein is
important because many genetic diseases result in
protein with abnormal aminoacid sequences,which
cause improper folding and loss or impairment of
normal function.
If the primary structure of normal and mutated
protein is known,this information may be used to
diagnose or study the disease.

32. Secondary structure of protein
Secondary structure, referrs to the local
conformation of some part of the polypeptide.
αHelix, β sheet, β Bends and motifs is
example of secondary structure of proteins.
Paul and Corey predicted the existence of
these secondary structures in 1951.

33. α HELIX
Several different types of helices but α
helix is the most abundant.
It is a spiral structure consisting of a tightly
packed, coiled polypeptide backbone
core,with the side chains of the component
aminoacids extending outward from the
central axis to avoid interfering sterically
with eachother.

34. Characteristics of α Helix
I t is right handed.
It is stablized by the extensive hydrogen
bonding between the peptide bond
carbonyl oxygens and amide hydrogens
that are part of polypeptide backbone.
The hydrogen bonding is present between
the successive first and fourth amino acid.

35. Each turn of the
αHelix contains 3.6
aminoacid.
Thus,aminoacid
residues spaced three
or four apart in the
primary sequence are
spatially close
together when folded
in the αhelix.

36. Five different kinds of constraints affect the stability of
an a helix:
1.The electrostatic repulsion (or attraction)
between successive amino acid residues
with charged R groups.
2.The bulkiness of adjacent R groups.
3.The interactions between amino acid
side chains spaced three (or four)
residues apart.
4.The occurrence of Pro and Gly residues.
5.The interaction between amino acid
residues at the ends of the helical
segment .

37. βSHEET
β SHEET is another form of secondary structure
in which all the peptide bond components are
involved in hydrogen bonding.
The surface of β sheet appear “pleated” and
therefore these structures are often called β
pleated sheets .
When illustrations are made of protein
structures, β strands are often visualized as broad
arrows.
The adjacent polypeptide chains in a β sheet can
be either parallel or antiparallel.

39. The b conformation of polypeptide chains. These top and
side views reveal the R groups extending out from the
b sheet and emphasize the pleated shape described by
the planes of the peptide bonds

40. βBENDS
β Bends reverse the direction of polypeptide
chain,helping it to form a compact globular shape.
In globular proteins, which have a compact folded
structure, nearly one-third of the amino acid residues
are in turns or loops where the polypeptide chain
reverses direction.
They are usually found on the surface of protein
molecule ,and often includes charged residues.

41. Particularly common are β turns that
connect the ends of two adjacent segments
of an antiparallel β sheet.
The structure is a 180º turn involving four
amino acid residues, with the carbonyl
oxygen of the first amino acid residue
forming a hydrogen bond with the amino-
group hydrogen of the fourth.

42. The peptide groups of the central two
residues in b turns do not participate in any
interresidue hydrogen bonding.
Gly and Pro residues often occur in b turns.

43. Structures of b turns

44. MOTIFS
Globular proteins are constructed by combining
secondary structural elements(α Helices,β sheet).

46. TERTIARY STRUCTURE OF
PROTEINS
Tertiary Structure describes the shapes
which form when the secondary spirals of
the protein chain further fold up on
themselves.
The overall three-dimensional
arrangement of all atoms in a protein.

47. DOMAINS are the fundamental functional
and three dimensional structural units of a
polypeptide.Polypeptide chains that are
greater than 200 aminoacids in length
consists of two or more domains.
The core of the domain is built from super
secondary elements(motifs)

48. Folding of the peptide chain within a
domain usually occurs independentlay of
folding in others domain.
Therefore each domain has a
characteristics of a small compact globular
protein that is structurally independent of
the other domains in the polypeptide chain.

50. Interactions stablizing tertiary structure
The unique three dimensional structure of
each polypeptide is determined by the
aminoacid sequence.Interactions between
the side chains of aminoacids guide the
folding of the polypeptide to form the
compact structure .
Four types of interactions cooperate in
stablizing the tertiary structure of globular
proteins.

51. Disulfide bond
Hydrophobic interactions
Hydrogen bonds
Ionic interactions

54. QUATERNARY STRUCTURE
 Some proteins contain two or more
separate polypeptide chains or
subunits.The arrangement of these protein
subunits in three-dimensional complexes
constitutes quaternary structure.
For example globin of hemoglobin is
made up of four subunit,Enzyme pyruvate
dehydrogenase is madeup of three
subunits

55. Protein undergo assisted folding
A specialized group of proteins, named chaperones
are required for the proper folding of many species of
proteins.
Molecular chaperones: Hsp 70, Hsp 40, Dna K, Dna J,
Grp E, chaperonins…etc.
Protein disulfide isomerase (PDI): catalyzes the
interchange or shuffling of disulfide bonds.
Peptide prolyl cis-trans isomerase (PPI): catalyzes the
interconversion of the cis and trans isomers of
proline peptide bonds.

56. Protein misfolding
Protein folding is a complex,trial and error
process that can some times result in
improperly folded molecules.
Deposits of misfolded proteins are
associated with a number of diseases
including
1.Amyloidoses
2.Prion disease