Chapter - 4Chapter - 4

Fibrous ProteinsFibrous Proteins

Lecture 7Lecture 7Contents:Contents:

OverviewOverview

Collagen:Collagen:– Types of collagenTypes of collagen

– Structure of collagenStructure of collagen

– Biosynthesis of collagenBiosynthesis of collagen

I. OVERVIEWI. OVERVIEW

CollagenCollagen and and elastinelastin are examples of are examples of common, well-characterized common, well-characterized fibrous fibrous proteinsproteins that serve structural functions that serve structural functions in the body. in the body.

For example, For example, collagencollagen and and elastinelastin are are found as components of found as components of skinskin, , connective tissueconnective tissue, , blood vessel wallsblood vessel walls, , and and sclerasclera and and corneacornea of the eye. of the eye.

Each fibrous proteinEach fibrous protein exhibits special exhibits special mechanical propertiesmechanical properties, resulting from , resulting from its unique structure, which are obtained its unique structure, which are obtained by combining specific amino acids into by combining specific amino acids into regular, secondary structural elementsregular, secondary structural elements. .

This is This is in contrast toin contrast to globular proteinsglobular proteins, , whose shapes are the result of complex whose shapes are the result of complex interactions interactions between secondary, between secondary, tertiary, and sometimes, quaternary tertiary, and sometimes, quaternary structural elementsstructural elements..

CollagenCollagen is is the most abundant protein the most abundant protein in the human bodyin the human body. .

A typical collagen moleculeA typical collagen molecule is a is a longlong, , rigid structurerigid structure in which in which three three polypeptidespolypeptides " "-chains" -chains" are wound are wound around one anotheraround one another in a in a rope-like rope-like triple-helix triple-helix (Figure 4.1).(Figure 4.1).

II. COLLAGENII. COLLAGEN

Although collagen molecules are found Although collagen molecules are found throughout the body, their types and throughout the body, their types and organization are dictated by the organization are dictated by the structural role collagen plays in a structural role collagen plays in a particular organ. particular organ.

In some tissuesIn some tissues, , collagencollagen may be may be dispersed as a geldispersed as a gel support to the support to the structure, as structure, as in the extracellular matrixin the extracellular matrix or the or the vitreous humor of the eyevitreous humor of the eye..

In other tissuesIn other tissues, , collagencollagen may be may be bundled bundled in tightin tight, , parallel fibersparallel fibers great strengthgreat strength, , as in as in tendonstendons. .

In the cornea of the eyeIn the cornea of the eye, , collagencollagen is is stackedstacked transmit light with a minimum transmit light with a minimum of scatteringof scattering. .

Collagen of boneCollagen of bone occurs as occurs as fibers fibers arranged at an angle to each otherarranged at an angle to each other resist mechanical shearresist mechanical shear from any from any direction.direction.

A. Types of collagenA. Types of collagen

The The collagen superfamilycollagen superfamily of proteins of proteins includes more than includes more than 20 collagen types20 collagen types, , and proteins that have collagen-like and proteins that have collagen-like domains. domains.

The three polypeptide The three polypeptide -chains-chains are are held held together bytogether by hydrogen bondshydrogen bonds between between the chains.the chains.

Variations in the amino acid sequence Variations in the amino acid sequence of the of the -chains-chains structural structural components that are about the same components that are about the same size size (approximately 1000 amino acids (approximately 1000 amino acids long),long), but with slightly different but with slightly different properties. properties.

These These -chains-chains are are combined to form combined to form the various types of collagenthe various types of collagen found in found in the tissues.the tissues.

the most common collagen:the most common collagen:

– Type IType I, , containscontains two chains two chains called called ll and and one chainone chain called called 22 ((11222)2)

– type IItype II collagen collagen containscontains three three ll chains chains ((1133).).

The collagensThe collagens can be organized into can be organized into three groupsthree groups, based on their location , based on their location and functions in the body and functions in the body (Figure 4.2).(Figure 4.2).

11 . .Fibril-forming collagensFibril-forming collagens::

TypesTypes II, , IIII, and , and IllIll are are the fibrillar the fibrillar collagenscollagens, and , and have the rope-like have the rope-like structurestructure described before for a typical described before for a typical collagen molecule. collagen molecule.

In the electron microscopeIn the electron microscope, these , these linear linear polymers of fibrilspolymers of fibrils have characteristic have characteristic banding patterns banding patterns reflecting the reflecting the regular staggered packingregular staggered packing of the of the individual collagen molecules in the individual collagen molecules in the fibril fibril (Figure 4.3).(Figure 4.3).

Type I collagen fibersType I collagen fibers are are found infound in supporting elements of high tensile supporting elements of high tensile strength (e.g. strength (e.g. tendon tendon andand cornea cornea).).

Fibers formed from type IIFibers formed from type II collagencollagen molecules are restricted to molecules are restricted to cartilaginous structurescartilaginous structures..

FibrilsFibrils derived from type Ill collagenderived from type Ill collagen are are prevalent in more distensible tissues, prevalent in more distensible tissues, such as such as blood vesselsblood vessels..

2. Network-forming collagens:2. Network-forming collagens:

TypesTypes IVIV and and VIIVII form a form a three-dimensional three-dimensional meshmesh, , rather than distinct fibrilsrather than distinct fibrils (Figure 4.4).(Figure 4.4).

For example, For example, type IVtype IV molecules assemble into a molecules assemble into a sheet or meshworksheet or meshwork that constitutes a major part that constitutes a major part of of basement membranesbasement membranes. .

[ Basement membranes [ Basement membranes areare thin, sheet-like thin, sheet-like structures structures that provide mechanical support for that provide mechanical support for adjacent cellsadjacent cells, , andand function as a semipermeable function as a semipermeable filtration barrier for macromolecules in organs filtration barrier for macromolecules in organs such as thesuch as the kidney kidney and theand the lung.] lung.]

33 . .Fibril-associated collagensFibril-associated collagens::

Types IX and XIITypes IX and XII bind to the surface bind to the surface of collagen fibrilsof collagen fibrils, , linking these fibrils linking these fibrils to one another and to one another and to other to other components in the components in the extracellular matrix extracellular matrix (Figure 4.2).(Figure 4.2).

B. Structure of collagenB. Structure of collagen

1. Amino acid sequence:1. Amino acid sequence: CollagenCollagen is is rich inrich in prolineproline and and glycineglycine, , both of which are important in the both of which are important in the formation of the formation of the triple-stranded helixtriple-stranded helix. .

ProlineProline facilitates the formation of facilitates the formation of the the helical conformation of each helical conformation of each --chainchain because its because its ring structurering structure "kinks""kinks" in the peptide chain. in the peptide chain.

GlycineGlycine, the , the smallest amino acidsmallest amino acid, is , is found infound in every third position of the every third position of the polypeptide chain. polypeptide chain.

It It fits into the restricted spacesfits into the restricted spaces where where the three chains of the helix come the three chains of the helix come together.together.

The The glycine residuesglycine residues are part of a are part of a repeating sequence. —repeating sequence. —GlyGly——XX——YY—, —, where where XX is frequently is frequently prolineproline and and YY is is often often hydroxyprolinehydroxyproline or or hydroxylysinehydroxylysine (Figure 4.5).(Figure 4.5).

Most of the Most of the .- chain.- chain can be regarded as can be regarded as a a polytripeptidepolytripeptide whose sequence can be whose sequence can be represented as (—represented as (—GlyGly——XX——YY—) —) 333333

22 . .Triple-helical structureTriple-helical structure:: Unlike most globular proteinsUnlike most globular proteins that are folded that are folded into compact structures, into compact structures, collagencollagen, , a fibrous a fibrous protein, has an elongated, triple-helical protein, has an elongated, triple-helical structurestructure that places many of its amino acid that places many of its amino acid side chains on the surface of the triple-side chains on the surface of the triple-helical molecule.helical molecule.

[This allows [This allows bond formationbond formation between the between the exposed R-groups of neighboring collagen exposed R-groups of neighboring collagen monomers monomers aggregation into long fibers]aggregation into long fibers]

33 . .Hydroxyproline and hydroxylysineHydroxyproline and hydroxylysine::

CollagenCollagen contains hydroxyproline contains hydroxyproline (hyp)(hyp) and hydroxylysineand hydroxylysine (hyl),(hyl), which are not which are not present in most other proteins. present in most other proteins.

These residuesThese residues result from the result from the hydroxylation of some of the proline and hydroxylation of some of the proline and lysine residueslysine residues after their incorporation after their incorporation into polypeptide chains into polypeptide chains

(Figure 4.6).(Figure 4.6).

The The hydroxylationhydroxylation is, thus, an example is, thus, an example of posttranslational modification .of posttranslational modification .

HydroxyprolineHydroxyproline is is important in important in stabilizing the triple-helical structurestabilizing the triple-helical structure of of collagencollagen because it maximizes because it maximizes interchain hydrogen bond formation.interchain hydrogen bond formation.

44 . .GlycosylationGlycosylation::

The The hydroxyl group of the hydroxyl group of the hydroxylysine residues of collagenhydroxylysine residues of collagen may may be enzymatically be enzymatically glycosylatedglycosylated. .

Most commonlyMost commonly, , glucoseglucose and and galactosegalactose are are sequentially attached to the sequentially attached to the polypeptide chainpolypeptide chain prior to triple-helix prior to triple-helix formation formation (Figure 4.7).(Figure 4.7).

C. Biosynthesis of collagenC. Biosynthesis of collagen

The polypeptide precursors of the The polypeptide precursors of the collagencollagen molecule are formed in molecule are formed in fibroblastsfibroblasts (or in the related (or in the related osteoblasts osteoblasts of of bonebone and and chondroblastschondroblasts of of cartilagecartilage), ), and are and are secreted into the extracellular secreted into the extracellular matrix. matrix.

After enzymic modificationAfter enzymic modification, , the mature the mature collagen monomers aggregatecollagen monomers aggregate and and become cross-linked become cross-linked collagen fibrilscollagen fibrils..

1. Formation of pro- 1. Formation of pro- -chains:-chains:

– CollagenCollagen is one of many proteins that is one of many proteins that normally function outside of cellsnormally function outside of cells. .

– Like most proteins produced for export, Like most proteins produced for export, the newly synthesized polypeptide the newly synthesized polypeptide precursors of precursors of -chains-chains contain a special contain a special amino acid sequenceamino acid sequence at their N-terminal at their N-terminal ends. ends.

– This This acts as a signalacts as a signal that the polypeptide that the polypeptide being synthesized is destined being synthesized is destined to leave the to leave the cell.cell.

– The The signal sequence:signal sequence:

facilitates the binding of ribosomes facilitates the binding of ribosomes to the rough endoplasmic reticulumto the rough endoplasmic reticulum (RER)(RER)

directs the passage of the directs the passage of the polypeptide chain into the cisternae polypeptide chain into the cisternae of the RERof the RER..

is rapidly cleaved in the endoplasmic is rapidly cleaved in the endoplasmic reticulum reticulum precursor of collagen precursor of collagen called a pro-called a pro--chain-chain (Figure 4.7).(Figure 4.7).

22 . .HydroxylationHydroxylation::

The The pro- pro- -chains-chains are are processed by a processed by a number of enzymic stepsnumber of enzymic steps within the within the lumen of the RERlumen of the RER while the while the polypeptides are still being synthesized polypeptides are still being synthesized (Figure 4.7).(Figure 4.7).

ProlineProline and and lysinelysine residues found in the residues found in the YY-position of the —-position of the —GlyGly——XX——YY— — sequence sequence can be hydroxylated can be hydroxylated hydroxyprolinehydroxyproline and and hydroxylysine hydroxylysine residues.residues.

These These hydroxylation hydroxylation reactionsreactions require require molecular oxygen molecular oxygen and and the reducing agentthe reducing agent vitamin Cvitamin C the hydroxylating the hydroxylating enzymes, enzymes, prolyl prolyl hydroxylasehydroxylase and and lysyl lysyl hydroxylasehydroxylase, are , are unable to function unable to function without vit. Cwithout vit. C

(Figure 4.6).(Figure 4.6).

In the case of vit.C deficiencyIn the case of vit.C deficiency (therefore, a (therefore, a lack of prolyl and lysyl hydroxylation),lack of prolyl and lysyl hydroxylation), collagen fiberscollagen fibers cannot be cross-linked, cannot be cross-linked, greatly greatly the tensile strength of the the tensile strength of the assembled fiberassembled fiber. .

Vit.C deficiencyVit.C deficiency disease known as disease known as scurvyscurvy. .

Patients with Patients with vit.C deficiencyvit.C deficiency often showoften show bruisesbruises on the limbs as a result of on the limbs as a result of subcutaneous extravasation of blood subcutaneous extravasation of blood ((capillary fragilitycapillary fragility) ) ( Figure 4.8)( Figure 4.8)

33 . .GlycosylationGlycosylation::

Some Some hydroxylysine hydroxylysine residues are residues are

modified bymodified by glycosylationglycosylation with with glucose glucose

or glucosyl-galactoseor glucosyl-galactose (Figure 4.7).(Figure 4.7).

44 . .Assembly and secretionAssembly and secretion::

After hydroxylation and glycosylationAfter hydroxylation and glycosylation, , pro-pro--chains -chains form procollagenform procollagen , , a precursor of collagen that has a a precursor of collagen that has a central region of triple helix flanked by central region of triple helix flanked by the non-helical amino- and carboxyl-the non-helical amino- and carboxyl-terminal extensions calledterminal extensions called propeptides.propeptides.

(Figure 4.7).(Figure 4.7).

The The formation of procollagenformation of procollagen begins withbegins with formation of interchain formation of interchain disulfide bondsdisulfide bonds between the C-terminal between the C-terminal extensions of the pro-extensions of the pro-- chains.- chains.

This This brings the three brings the three -chains into an -chains into an alignment favorable for helix formation.alignment favorable for helix formation.

TheThe procollagen procollagen molecules are molecules are translocated to the Golgi apparatustranslocated to the Golgi apparatus, , where they are where they are packaged in secretory packaged in secretory vesicles.vesicles.

The The vesiclesvesicles fuse with the cell fuse with the cell membranemembrane release of procollagen release of procollagen molecules into the extracellular spacemolecules into the extracellular space..

55 . .Extracellular cleavage of Extracellular cleavage of procollagen moleculesprocollagen molecules::

After their releaseAfter their release, , the procollagen the procollagen moleculesmolecules are are cleaved bycleaved by N - and C N - and C – pro - collagen peptidases– pro - collagen peptidases remove remove the terminal propeptidesthe terminal propeptides releasing releasing triple-helical collagen moleculestriple-helical collagen molecules..

66 . .Formation of collagen fibrilsFormation of collagen fibrils::

Individual collagen moleculesIndividual collagen molecules spontaneously spontaneously associateassociate form form fibrilsfibrils. .

They They form form an an orderedordered, , overlap pingoverlap ping, , parallel arrayparallel array, , with adjacent collagen with adjacent collagen moleculesmolecules arranged in a staggered arranged in a staggered pattern.pattern.

Each collagen moleculeEach collagen molecule overlaps its overlaps its neighborneighbor by three-quarters of its length. by three-quarters of its length.

(Figure 4.7).(Figure 4.7).

77 . .Cross-link formationCross-link formation::

The The fibrillar array of collagenfibrillar array of collagen molecules molecules servesserves as as a substrate for a substrate for lysyl oxidaselysyl oxidase. .

This This extracellular enzymeextracellular enzyme oxidatively oxidatively deaminates some of the lysyl and deaminates some of the lysyl and hydroxylysyl residueshydroxylysyl residues in collagen. in collagen.

The The reactive aldehydesreactive aldehydes that result that result ((allysineallysine and and hydroxyallysinehydroxyallysine) ) condense withcondense with lysyl or hydroxylysyl lysyl or hydroxylysyl residues in neighboring collagenresidues in neighboring collagen molecules molecules form covalent form covalent cross-linkscross-links (Figure 4.9).(Figure 4.9).

This This cross-linkingcross-linking is essential for is essential for achieving the achieving the tensile strength necessary for the proper tensile strength necessary for the proper functioning of connective tissuefunctioning of connective tissue. .

Any mutation Any mutation that interferes with the ability of that interferes with the ability of collagen to form cross-linked fibrilscollagen to form cross-linked fibrils affects affects the stability of the collagen].the stability of the collagen].

Lecture 8Lecture 8

Contents:Contents:

Degradation of collagenDegradation of collagen

Collagen diseases Collagen diseases

(Osteogenesis Imperfecta) (Osteogenesis Imperfecta)

D. Degradation of collagenD. Degradation of collagen

Normal collagensNormal collagens are are highly stablehighly stable molecules, molecules, having half-lives as long as having half-lives as long as several monthsseveral months. .

However, However, connective tissueconnective tissue is is dynamic dynamic and is and is constantly being remodeledconstantly being remodeled, , often in response to growth or injury of often in response to growth or injury of the tissue.the tissue.

Breakdown of collagen fibrilsBreakdown of collagen fibrils is is dependent on the proteolytic action ofdependent on the proteolytic action of collagenasescollagenases, which are part of a large , which are part of a large family of matrix family of matrix metalloproteinasesmetalloproteinases. .

Type I collagenType I collagen : the : the cleavage site is cleavage site is specificspecific, , generatinggenerating three-quarter three-quarter and and one-quarter lengthone-quarter length fragments. fragments.

These These fragmentsfragments are further are further degraded by degraded by other matrix proteinasesother matrix proteinases to their to their constituent amino acids.constituent amino acids.

E. Collagen diseasesE. Collagen diseases

DefectsDefects in any one of the many steps in any one of the many steps in in collagen fiber synthesiscollagen fiber synthesis genetic genetic diseasedisease inability of collagen to form inability of collagen to form fibers properlyfibers properly and and provide tissues provide tissues with the needed tensile strengthwith the needed tensile strength normally provided by collagen.normally provided by collagen.

> 1000 mutations> 1000 mutations have been identified have been identified in 22 genesin 22 genes coding for 12 of the coding for 12 of the collagen types. collagen types.

The following are examples of diseases The following are examples of diseases that are the result of defective collagen that are the result of defective collagen synthesis.synthesis.

Osteogenesis Imperfecta (OI)Osteogenesis Imperfecta (OI)::

This disease, known as This disease, known as brittle bone brittle bone syndromesyndrome, is also a , is also a heterogeneous heterogeneous group of inherited disordersgroup of inherited disorders distinguished by distinguished by bones that easily bones that easily bend and fracture bend and fracture (Figure 4.11).(Figure 4.11).

Retarded wound healingRetarded wound healing and a and a rotated rotated andand twisted spinetwisted spine ‘ ‘humped-backhumped-back” ” appearance are common features of the appearance are common features of the disease.disease.

Type I OIType I OI is called is called osteogenesis osteogenesis imperfecta tarda. imperfecta tarda.

This disease :This disease :– presents in presents in early infancy.early infancy.

– fractures secondary to minor traumafractures secondary to minor trauma. .

– may be may be suspected if prenatal suspected if prenatal ultrasound detects bowing or ultrasound detects bowing or fractures of long bonesfractures of long bones..

Type II OIType II OI, (, (osteogenesis imperfecta osteogenesis imperfecta congenita)congenita)::

– more more severesevere

– patients patients die die inin uteroutero or in the or in the neonatal period of neonatal period of pulmonary pulmonary hypoplasiahypoplasia. .

– Most patients with severe OI have Most patients with severe OI have mutations in the gene for either the mutations in the gene for either the pro 1- or pro2- pro 1- or pro2- -chains of type I -chains of type I collagencollagen..

The The most common mutationsmost common mutations substitution of single amino acidssubstitution of single amino acids with with bulky side chains bulky side chains for the glycine residuesfor the glycine residues that appear as every third amino acid in that appear as every third amino acid in the triple helix. the triple helix.

The The structurally abnormal pro - structurally abnormal pro - -chains-chains

prevent folding prevent folding of the proteinof the protein into a into a triple-helical conformation.triple-helical conformation.

Lecture 9Lecture 9Contents:Contents:

ElastinElastin– Structure of elastinStructure of elastin

– Role of Role of 11-antitrypsin in elastin -antitrypsin in elastin

degradationdegradation

ELASTINELASTIN

In contrast to collagenIn contrast to collagen, which forms , which forms fibers that are fibers that are toughtough and have and have highhigh tensile strengthtensile strength, , ElastinElastin is a is a connective tissue proteinconnective tissue protein with with rubber-like properties.rubber-like properties.

Elastic fibersElastic fibers composed of elastin and composed of elastin and glycoprotein microfibrils are glycoprotein microfibrils are found infound in thethe lungs lungs, the , the walls of large arterieswalls of large arteries, , and and elastic ligamentselastic ligaments. .

They They can be stretchedcan be stretched to several times to several times their normal length, but their normal length, but recoil to their recoil to their original shapeoriginal shape when the stretching when the stretching force is relaxed.force is relaxed.

A. Structure of elastinA. Structure of elastin

ElastinElastin is is

– an an insoluble protein polymerinsoluble protein polymer

– synthesized fromsynthesized from a precursor, a precursor, tropoelastintropoelastin, ( a linear polypeptide , ( a linear polypeptide composed of about 700 amino acids that composed of about 700 amino acids that are primarily small and nonpolar)are primarily small and nonpolar) (e.g. (e.g. glycineglycine, , alaninealanine, and , and valinevaline).).

ElastinElastin is also, is also,– rich in proline and lysinerich in proline and lysine,,– containscontains a little hydroxyproline a little hydroxyproline – contains contains no hydroxylysineno hydroxylysine. .

TropoelastinTropoelastin is is secreted by the cellsecreted by the cell into the into the extracellular space.extracellular space.

There, it There, it interacts withinteracts with specific specific glycoprotein glycoprotein microfibrilsmicrofibrils, such as , such as fibrillinfibrillin, which function , which function as a as a scaffoldscaffold onto which tropoelastin is onto which tropoelastin is depositeddeposited. .

Mutations in the fibrillin gene Mutations in the fibrillin gene are responsible are responsible forfor Marfan’s syndromeMarfan’s syndrome

Some of the lysyl side chainsSome of the lysyl side chains of the of the tropoelastin polypeptides are tropoelastin polypeptides are oxidatively oxidatively deaminated by lysyl oxidasedeaminated by lysyl oxidase forming forming allysine residuesallysine residues. .

3 of the allysyl side chains3 of the allysyl side chains + + one unaltered one unaltered lysyl side chainlysyl side chain from the same or from the same or neighboring polypeptides neighboring polypeptides form a form a desmosine cross-link.desmosine cross-link. (Figure 4.12).(Figure 4.12).

This produces This produces ElastinElastin - an - an extensively extensively interconnectedinterconnected, , rubbery networkrubbery network that that can stretch can stretch and bend in any directionand bend in any direction when stressed when stressed connective tissue elasticityconnective tissue elasticity

(Figure 4.13).(Figure 4.13).

B. Role of B. Role of 11-antitrypsin in -antitrypsin in

elastin degradationelastin degradation

1.1. 11-antitrypsin:-antitrypsin:

BloodBlood and other body fluids and other body fluids containcontain a proteina protein, , 11- antitrypsin- antitrypsin ( (11-AT-AT) or ) or ( ( 11-antiproteinase-antiproteinase) ) inhibitsinhibits a a number of proteolytic enzymes number of proteolytic enzymes ((proteasesproteases or or proteinasesproteinases) ) hydrolyze and destroy proteinshydrolyze and destroy proteins. .

[The inhibitor [The inhibitor was originally namedwas originally named 11--

antitrypsin antitrypsin becausebecause it inhibits the it inhibits the activity of trypsin (activity of trypsin (a proteolytic enzyme a proteolytic enzyme synthesized as trypsinogen by the synthesized as trypsinogen by the pancreaspancreas]]

11- AT- AT comprises comprises > 90% of the > 90% of the

11-globulin fraction-globulin fraction of normal plasma. of normal plasma.

11- AT- AT has the has the important important physiologic physiologic

role of inhibiting neutrophil role of inhibiting neutrophil elastase elastase - - a powerful protease that is released a powerful protease that is released into the extracellular space, and into the extracellular space, and degrades elastin of alveolar wallsdegrades elastin of alveolar walls, as , as well as other structural proteins in a well as other structural proteins in a variety of tissues variety of tissues (Figure 4.14).(Figure 4.14).

Most of the Most of the 11-AT-AT found in plasma is found in plasma is synthesized and secreted by the liversynthesized and secreted by the liver. .

The remainderThe remainder is synthesized by is synthesized by several tissues, including several tissues, including monocytes monocytes and alveolar macrophagesand alveolar macrophages, which may , which may be important in the be important in the prevention of local prevention of local tissue injury by elastasetissue injury by elastase..

22 . .Role of Role of 11-AT in the lungs-AT in the lungs::

In the normal lungIn the normal lung, the , the alveoli alveoli are are chronically exposed to chronically exposed to low levels of low levels of neutrophil elastaseneutrophil elastase released from released from activated and degenerating neutrophils. activated and degenerating neutrophils.

This proteolytic activityThis proteolytic activity can can destroy the destroy the elastin in alveolar wallselastin in alveolar walls if unopposed by the if unopposed by the

inhibitory action ofinhibitory action of 11-AT-AT ( the most important ( the most important

inhibitor of neutrophil elastase)inhibitor of neutrophil elastase)

(Figure 4.14).(Figure 4.14).

Because lung tissue cannot Because lung tissue cannot regenerateregenerate, , emphysemaemphysema results results from the destruction of the from the destruction of the connective tissue of alveolar walls.connective tissue of alveolar walls.

33 . .Emphysema resulting from Emphysema resulting from 11-AT -AT

deficiencydeficiency::

In USA, In USA, inherited defects in inherited defects in 11-AT-AT 2-5% 2-5% of patients having of patients having emphysemaemphysema. .

A number of A number of different mutationsdifferent mutations in the in the 11-AT gene-AT gene deficiency of this protein, deficiency of this protein,

but one single purine base mutation but one single purine base mutation (GAG (GAG AAG, AAG, substitution of lysine for substitution of lysine for glutamic acid at position 342 of the glutamic acid at position 342 of the proteinprotein) is clinically the most widespread.) is clinically the most widespread.

An individualAn individual must inherit 2 abnormal must inherit 2 abnormal 11- AT alleles to be at risk- AT alleles to be at risk for the for the

development of development of emphysemaemphysema. .

In a heterozygote In a heterozygote (with one normal (with one normal and one defective gene) and one defective gene) the levels of the levels of 11-AT-AT are are sufficient to protect the sufficient to protect the

alveoli from damagealveoli from damage..

A specific A specific 11-AT methionine -AT methionine is required is required

for thefor the binding of the inhibitor to its target binding of the inhibitor to its target proteases. proteases.

SmokingSmoking oxidation oxidation andand subsequent subsequent inactivation of thatinactivation of that methionine residue, methionine residue, render the inhibitor powerless to render the inhibitor powerless to neutralize elastaseneutralize elastase. .

SmokersSmokers with with 1 1 -AT deficiency-AT deficiency, have, have

rate of lung destruction rate of lung destruction poorer survival poorer survival rate rate than nonsmokers with the deficiencythan nonsmokers with the deficiency..

The The deficiency ofdeficiency of elastase inhibitorelastase inhibitor can be reversedcan be reversed by by weekly IV weekly IV administration of administration of 11-AT. -AT.

The The 11-AT-AT diffuses from the blood diffuses from the blood

into the lunginto the lung, where it reaches , where it reaches therapeutic levels in the fluid therapeutic levels in the fluid surrounding the lung epithelial surrounding the lung epithelial cells.cells.

THE ENDTHE END