Chemistry Reference
In-Depth Information
structure. This must relate to the function of the C-propeptide (NC1) domains in the
assembly of the trimeric molecules, to be discussed below.
Molecular assembly of the Type I collagen molecule
The COL1A1 and COL1A2 terminology relates to the polypeptide chain that is the
product of the translation of the entire final processed messenger RNA. Since each chain
is itself a multi-domain structure that is post-translationally processed into the final
functional units during the initial three chain association into molecules, the subsequent
export into the extracellular space, and the assembly into tissue specific fibrillar arrays, a
different nomenclature was developed. The individual biosynthetic products, with all
domains intact, are designated as pro-alpha chains, pro-
2(I), respectively.
The normal type I procollagen heterotrimer (with all domains intact) has the formula
([pro
α
1(I) and pro-
α
1(I)]
3
also is formed, but only a small
fraction of the collagen assembles in this fashion. The potential homotrimer [pro
α
1(I)]
2
pro
α
2(I)). The homotrimer [pro
α
α
2(I)]
3
does not appear to exist naturally.
Figure 7 provides a schematic overview of the pro
2(I) chain domain
arrangements and domain sizes. The central domain of 338 GXY amino acid repeats that
fold into the uninterrupted triple helix structure is identical in length in each chain, but the
sequences (G is always in the proper position, but X and Y differ between chains) are not.
Regions or subdomains with special reactivity or properties exist even within the
uninterrupted triple helix and these areas are also denoted specifically. Lysine residues (K)
that ultimately participate in cross-linking reactions are depicted by the heavy arrows at
residues K87 in both chains and at residue K930 in the
α
1(I) and pro-
α
2 chain can
also participate in cross-linking. The remaining domains differ in sequence and size.
Assembly of the ribosomes and translation of the mRNA begins in the cytosol. Following
elaboration of the signal peptide sequences translation is paused until the signal peptides
find their receptors on the endoplasmic reticulum (ER). After the signal peptides insert the
nascent chains into the ER cisternal space, chain synthesis and elongation resume within the
restricted ER space and environment, Figure 8. The growing chains remain in the unfolded
state until elongation is essentially completed. As they grow the separate chains are subject
to a number of interactions and post-translational modifications that modulate the chain
properties and prepare them for their ultimate functionality. One important interaction is
with an ER-resident chaperone, heat-shock protein Hsp 47, which reacts specifically with
the nascent
α
1 chain. K933 in the
α
1 N-propeptide, and perhaps other parts of the chain, to prevent premature
interchain interaction and random collagen-fold formation (Hu et al. 1995). Koide et al
(2002) have shown that, within the ER, HSP 47 binds to the newly formed triple helix,
stabilizing the structure until helix formation is complete and is ready for export to the
Golgi. Chaperone proteins have the function of preventing misfolding of nascent protein
chains. HSP 47 is uniquely a chaperone for collagen. Although it has been known for a long
time that full length collagen chains properly in register can form triple-helix in either
direction, i.e., N C or N
α
C (Veis and Cohen 1960; Drake and Veis 1964; Frank et al.
2003),
in vivo
the triple helical folding is in the C N direction (Bruckner et al. 1981,
Bachinger et al. 1980), following completion of elongation and registration of the C-
propeptides. Recent studies show that this registration is a very complex process.
The principal modification during chain elongation is that of the hydroxylation of
selected proline residues in the Y positions of the repetitive GXY sequences. In this
potential helical domain, the sequence GPP occurs frequently. The second (Y-position) P
is subject to the action of the enzyme prolyl hydroxylase that places a hydroxyl group on
the 4-position of the P pyrrolidine ring. This crucial reaction is both tissue and species
specific and regulates the stability of the final triple helix. An unhydroxylated chain will
not join into the three chain triple helical structure of collagen at body temperature. That
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