section
ii.i
Protein Fibers and Proteoglycans
181
-Lys-Ala-Ala-Lys- The clustering of lysine residues
with alanine residues provides the appropriate geometry
for the formation of cross-links. Cross-linking elastin oc-
curs extracellularly. The polypeptides are synthesized in-
tracellularly by connective tissue cells (such as smooth
muscle cells), according to the same principles for the
formation of other export proteins (e.g., collagen; see
Chapter 25). After transport into the extracellular space,
the polypeptides undergo crosslinking. A key step is
the oxidative deamination of certain lysyl residues, cat-
alyzed by lysyl oxidase (a Cu2+ protein). These ly-
syl residues are converted to very reactive aldehydes
(a-aminoadipic acid 5-semialdehyde) known as allysine
residues. Through an unknown mechanism, three ally-
sine residues and one unmodified lysine residue react
to form a pyridinium ring, alkylated in four positions,
which is the basis for the cross-links (Figure 11-5).
The cross-links may occur within the same polypep-
tide or involve two to four different polypeptide chains.
Current models of elastin structure suggest that only
two polypeptide chains are required to form the desmo-
sine cross-link, one chain donating a lysine and an ally-
sine residue, the other contributing two allysine residues.
Elastin polypeptides are also cross-linked by condensation
of a lysine residue with an allysine residue, followed by re-
duction of the aldimine to yield a lysinonorleucine residue
(Figure 11-6). These linkages are present to a much lesser
extent than in collagen.
Formation of cross-linkages in elastin can be prevented
by inhibition of lysyl oxidase. Animals maintained on a
copper-deficient diet and those administered lathyrogens
such as /3-aminopropionitrile or a-aminoacetonitrile de-
velop connective tissue abnormalities. Fathyrogens are
so-called because of their presence in certain peas of the
genus
Lathyrus.
They are noncompetitive inhibitors of ly-
syl oxidase, both
in vitro
and
in vivo.
Consumption of
certain types of sweet pea (e.g.,
Lathyrus odoratus
) can
lead to lathyrism. In osteolathyrism, the abnormalities
involve bone and other connective tissues, the responsi-
ble compounds being the above-mentioned nitrites. The
toxic agent responsible for neurolathyrism, /3-N-oxalyl-L-
a,/J-diaminopropionic acid, has been isolated from
Lath-
yrus sativus
but its mode of action is not known. Thus,
copper deficiency or administration of lathyrogens in
animals prevents the formation of the highly insoluble
cross-linked elastin but results in the accumulation of
soluble elastin. Soluble elastin obtained in this manner
is particularly useful in structural studies. Purification of
the insoluble elastin without disruption of the integrity
of the polypeptide chains is a formidable task.
Several models of the macromolecular structure of
elastin have been suggested to account for its elasti-
city: cross-linked globular elastin subunits, cross-linked
o=c
H — N
o=c
o=c
H— N
,c=o
N— H
c=o
N— H
,C
= 0
N— H
Lysinonorleucine
cross-link
FIGURE 11-6
Formation of the lysinonorleucine cross-link between an allysine and a
lysine residue in elastin.
random elastin chains, the oiled-coil model, and the fibril-
lar model. The fibrillar model incorporates a unique con-
formation due to the presence of a glycine residue fol-
lowed by an amino acid residue with a bulky R-group
(e.g., Pro-Gly-Gly-Val). This type of sequence gives
rise to near right angle turns (/3-turns; Chapter 4) in the
polypeptide backbone. The oiled-coil model assumes that
each polypeptide chain is fibrillar and consists of alter-
nating segments of cross-linked regions and “oiled coils,”
each chain being linked to many others to form a three-
dimensional network similar to a mattress spring. It is pos-
tulated that these coils can stretch up to 2-2.5 times their
original length. The driving force for recoil of elastic fibers
is due to a change in entropy.
T u rn over o f E la stin
The turnover rate of mature elastin in healthy persons is
relatively low. Insoluble elastin in healthy elastic tissue is
usually stable and subjected to minimal proteolytic degra-
dation. In several clinical conditions (e.g., emphysema,
advanced atherosclerosis, pancreatitis), increased degra-
dation of fragmentation of elastic fibers may play a signif-
icant role. The interaction between insoluble elastin and
soluble elastolytic enzymes, and the regulation of these en-
zymes, may shed light on certain cardiovascular diseases,
in view of the role of elastin in arterial dynamics.
