Molecular Cell Biology. 4th version.
The Primary Structural Unit of Collagen Is a Triple Helix
As a result of its abundance in tendon-rich tissue reminiscent of rat tail makes the fibrous
kind I collagen straightforward to isolate, it was the primary to be characterised. Its
basic structural unit is a protracted (300-nm), skinny (1.5-nm-diameter) protein
that consists of three coiled subunits: two α1(I) chains and one
α2(I).* Every chain accommodates exactly 1050 amino acids wound round each other in
a attribute right-handed triple helix (Determine 22-11a). All collagens have been ultimately proven to comprise
three-stranded helical segments of comparable construction; the distinctive properties of
every kind of collagen are due primarily to segments that interrupt the triple helix
and that fold into different kinds of three-dimensional buildings.
The triple-helical construction of collagen arises from an uncommon abundance of
three amino acids: glycine, proline, and hydroxyproline. These amino acids make
up the attribute repeating motif Gly-Professional-X, the place X might be any amino acid.
Every amino acid has a exact perform. The facet chain of glycine, an H atom, is
the one one that may match into the crowded heart of a three-stranded helix.
Hydrogen bonds linking the peptide bond NH of a glycine residue with a peptide
carbonyl (C═O) group in an adjoining polypeptide assist maintain the three
chains collectively. The mounted angle of the C – N
peptidyl-proline or peptidyl-hydroxyproline bond permits every polypeptide chain
to fold right into a helix with a geometry such that three polypeptide chains can
twist collectively to kind a three-stranded helix. Apparently, though the inflexible
peptidyl- proline linkages disrupt the packing of amino acids in an α
helix, they stabilize the inflexible three-stranded collagen helix.
Collagen Fibrils Type by Lateral Interactions of Triple Helices
Many three-stranded kind I collagen molecules pack collectively side-by-side, forming
fibrils with a diameter of fifty – 200 nm. In
fibrils, adjoining collagen molecules are displaced from each other by 67 nm,
about one-quarter of their size (Determine
22-11b). This staggered array produces a striated impact that may be
seen in electron micrographs of stained collagen fibrils; the attribute
sample of bands is repeated about each 67 nm (Determine 22-11c). The distinctive properties of the fibrous
collagens — sorts I, II, III, and
V — are as a result of skill of the rodlike triple
helices to kind such side-by-side interactions.
Quick segments at both finish of the collagen chains are of specific significance
within the formation of collagen fibrils (see Determine 22-11). These segments don’t assume the triple-helical
conformation and comprise the weird amino acid hydroxylysine
(see Determine 3-16). Covalent aldol
cross-links kind between two lysine or hydroxylysine residues on the C-terminus
of 1 collagen molecule with two related residues on the N-terminus of an
adjoining molecule (Determine 22-12). These
cross-links stabilize the side-by-side packing of collagen molecules and
generate a robust fibril.
Kind I collagen fibrils have monumental tensile power; that’s, such collagen
might be stretched with out being damaged. These fibrils, roughly 50 nm in diameter
and several other micrometers lengthy, are packed side-by-side in parallel bundles,
known as collagen fibers, in tendons, the place they join muscular tissues
with bones and should stand up to monumental forces (Determine 22-13). Gram for gram, kind I collagen is stronger than
metal.
Meeting of Collagen Fibers Begins within the ER and Is Accomplished exterior the
Cell – “collagen is which protein”
Collagen biosynthesis and meeting follows the traditional pathway for a secreted
protein (see Determine 17-13). The collagen
chains are synthesized as longer precursors known as
procollagens; the rising peptide chains are
co-translationally transported into the lumen of the tough endoplasmic reticulum
(ER). Within the ER, the procollagen chain undergoes a collection of processing
reactions (Determine 22-14). First, as with
different secreted proteins, glycosylation of procollagen happens within the tough ER and
Golgi complicated. Galactose and glucose residues are added to hydroxylysine
residues, and lengthy oligosaccharides are added to sure asparagine residues in
the C-terminal propeptide, a phase on the C-terminus of a
procollagen molecule that’s absent from mature collagen. (The N-terminal finish
additionally has a propeptide.) As well as, particular proline and lysine residues within the
center of the chains are hydroxylated by membrane-bound hydroxylases. Lastly,
intrachain disulfide bonds between the N- and C-terminal propeptide sequences
align the three chains earlier than the triple helix kinds within the ER. The central
parts of the chains zipper from C- to N-terminus to kind the triple
helix.
After processing and meeting of kind I procollagen is accomplished, it’s secreted
into the extracellular house. Throughout or following exocytosis, extracellular
enzymes, the procollagen peptidases, take away the N-terminal and C-terminal
propeptides. The ensuing protein, typically known as tropocollagen
(or just collagen), consists virtually solely of a
triple-stranded helix. Excision of each propeptides permits the collagen
molecules to polymerize into regular fibrils within the extracellular house (see
Determine 22-14). The doubtless
catastrophic meeting of fibrils throughout the cell doesn’t happen each as a result of the
propeptides inhibit fibril formation and since lysyl oxidase, which catalyzes
formation of reactive aldehydes, is an extracellular enzyme (see Determine 22-12). As famous above, these
aldehydes spontaneously kind particular covalent cross-links between two
triple-helical molecules, which stabilizes the staggered array attribute of
collagen molecules and contributes to fibril power.
Put up-translational modification of
procollagen is essential for the formation of mature collagen molecules and their
meeting into fibrils. Defects on this course of have severe penalties, as
historical mariners ceaselessly skilled. For instance, the exercise of each
prolyl hydroxylases requires a necessary cofactor, ascorbic acid (vitamin C).
In cells disadvantaged of ascorbate, as within the illness scurvy, the
procollagen chains are usually not hydroxylated sufficiently to kind secure triple
helices at regular physique temperature (Determine
22-15), nor can they kind regular fibrils. Consequently,
nonhydroxylated procollagen chains are degraded throughout the cell. With out the
structural help of collagen, blood vessels, tendons, and pores and skin turn out to be fragile.
A provide of recent fruit gives ample vitamin C to course of procollagen
correctly.
Mutations in Collagen Reveal Elements of Its Construction and
Biosynthesis
Kind I collagen fibrils are used because the
reinforcing rods in building of bone. Sure mutations within the
α1(I) or α2(I) genes result in
osteogenesis imperfecta, or brittle-bone illness. Probably the most
extreme kind is an autosomal dominant, deadly illness leading to loss of life in utero
or shortly after delivery. Milder kinds generate a extreme crippling illness. As
may be anticipated, many circumstances of osteogenesis imperfecta are resulting from deletions of
all or a part of the very lengthy α1(I) gene. Nonetheless, a single
amino acid change is ample to trigger sure types of this illness. As we
have seen, a glycine should be at each third place for the collagen triple
helix to kind; mutations of glycine to virtually another amino acid are
deleterious, producing poorly fashioned and unstable helices. Because the triple
helix kinds from the C- to the N-terminus, mutations of glycine close to the
C-terminus of the α1(I) chain are often extra deleterious
than these close to the N-terminus; the latter allow substantial areas of triple
helix to kind. Mutant unfolded collagen chains don’t go away the tough ER of
fibroblasts (the cells that make most of kind I collagen), or they go away it
slowly. Because the ER turns into dilated and expanded, the secretion of different proteins
(e.g., kind III collagen) by these cells is also slowed down.
As a result of every kind I collagen molecule accommodates two α1(I) and
one α2(I) chains, mutations within the
α2(I) chains are a lot much less damaging. To know this
level, think about that in a heterozygote expressing one wild-type and one mutant
α2(I) protein, 50 p.c of the collagen molecules
could have the irregular α2(I) chain. In distinction, if the
mutation is within the α1(I) chain, 75 p.c of the collagen
molecules could have one or two mutant α1(I) chains. In
reality, even low expression of a mutant α1(I) gene might be
deleterious, as a result of the mutant chains can disrupt the perform of wild-type
α1(I) chains when mixed with them. To check such
mutations, experimenters constructed a mutant α1(I)
collagen gene with a glycine-to-cysteine substitution close to the C-terminus. This
mutant gene was used to create strains of transgenic mice with in any other case regular
collagen genes. Excessive-level expression of the mutant transgene was deadly, and
expression at a fee 10 p.c that of the traditional α1(I)
genes brought on extreme progress abnormalities.
Collagens Type Various Constructions
Collagens differ of their skill to kind fibers and to prepare the fibers into
networks. For instance, kind II is the most important collagen in cartilage. Its fibrils
are smaller in diameter than kind I and are oriented randomly within the viscous
proteoglycan matrix. Such inflexible macromolecules impart a power and
compressibility to the matrix and permit it to withstand massive deformations in
form. This property permits joints to soak up shocks.
Kind II fibrils are cross-linked to proteoglycans within the matrix by kind IX, a
collagen of a distinct construction (Determine
22-16a). Kind IX collagen consists of two lengthy triple helices
related by a versatile kink. The globular N-terminal area extends from the
composite fibrils, as does a heparan sulfate molecule, a kind of enormous, extremely
charged polysaccharide (mentioned later) that’s linked to the
α2(IX) chain on the versatile kink. These protruding
nonhelical domains are thought to anchor the fibril to proteoglycans and different
parts of the matrix. The interrupted triple-helical construction of kind IX
collagen prevents it from assembling into fibrils; as a substitute, these three
collagens affiliate with fibrils fashioned from different collagen sorts and thus are
known as fibril-associated collagens (see Desk 22-3).
In lots of connective tissues, kind VI collagen is sure to the edges of kind I
fibrils and should bind them collectively to kind thicker collagen fibers (Determine 22-16b). Kind VI collagen is
uncommon in that the molecule consists of comparatively quick triple-helical areas
about 60 nm lengthy separated by globular domains about 40 nm lengthy. Fibrils of pure
kind VI collagen thus give the impression of beads on a string.
In some locations, a number of ECM parts are organized right into a basal lamina, a skinny sheetlike
construction. Kind IV collagen kinds the fundamental fibrous two-dimensional community of
all basal laminae. Three kind IV collagen chains kind a 400-nm-long triple helix
with massive globular domains on the C-termini and smaller ones of unknown
construction on the N-termini. The helical phase is uncommon in that the Gly-X-Y
sequences are interrupted about 24 occasions with segments that can’t kind a triple
helix; these nonhelical areas introduce flexibility into the molecule (Determine 22-17a). Lateral affiliation of the
N-terminal areas of 4 kind IV molecules yields a attribute tetrameric
unit that may be noticed within the electron microscope (Determine 22-17b). Triple-helical areas from a number of
molecules then affiliate laterally, in a way much like fibril formation
amongst fibrous collagens, to kind branching strands of variable however skinny
diameters. These interactions, along with these between the C-terminal
globular domains and the triple helices in adjoining kind IV molecules, generate
an irregular two-dimensional fibrous community (Determine 22-17b). We are going to talk about the opposite parts of the basal
lamina and the features of this specialised matrix construction within the subsequent
part.
“collagen is which protein”