Collagen post-translational modification

The final steps of collagen post-translational modification, including assembly of colleen fibrils and collagen fibers, occur after the protein has been secreted from the cell. 

Very few post-translational modifications have been found on tropoelastin. However, hydroxylation of 25% of the proline residues is observed [10]. The enzymatic modification of proline to hydroxyproline (Hyp) is performed by prolyl hydroxylase [11]. The purpose of this hydroxylation remains unclear and it is even proposed that Hyps in tropoelastin are a by-product of collagen hydroxylation as this occurs in the same cellular compartment [8]. 

Catalysts of Collagen Folding, Co- and Post-Translational Modification... 

Some proteins, like collagen and elastin, have covalent cross-links between their fibres, which are formed after their synthesis (post-translational modification). 

The many (possibly more than 30) types of collagens found in human connective tissues have substantially the same chemical structure consisting mainly of glycine with smaller amounts of proline and some lysine and alanine. In addition, there are two unusual amino acids, hydroxyproline and hydroxylysine, neither of which has a corresponding base-triplet or codon within the genetic code. There is therefore, extensive post-translational modification of the protein by hydroxylation and also by glycosylation reactions. 

The precursor molecule of collagen (preprocollagen), formed in the rER, is subject to extensive post-translational modifications (see p. 232) in the ER and Golgi apparatus. 

C. Much of collagen s strength arises from the special mechanism of its synthesis, post-translational modification, and assembly into collagen fibers (Figure 2-3). 

A procollagen triple helix is assembled in the endoplasmic reticulum helix formation is aided by disulfide bonds between N- and C-terminal propeptides, which align the polypeptide chains. Post-translational modification of procollagen is crucial in allowing for collagen fibril formation. For example, in cells deprived of ascorbate, as in the disease scurvy, the procollagen chains are not hydroxylated sufficiently to form stable triple helices at normal body temperature (hydrox-ylation is through the activity of prolyl hydroxylase, which requires the cofactor ascorbic acid). 

The second (functional) aspect of this problem eoneems the development of pathologic symptoms, the moleeular causes of which are not due to AChE inhibition. One of the first cases of OP nonanticholinesterase effeets (when the association between the OP molecular target and the functional disturbance has been proved) involved inhibition of kinurenin formamidase of the hen egg yolk sac membrane responsible for teratogenic effects (Seifert and Casida, 1978). Another example of OP teratogenic effect is abnormal development of the conjunctival tissue of Xen-opus embryos due to inhibition of lysyloxidase and incomplete post-translational modification of collagen (Snawder and Chambers, 1993). 

Deficiency in vitamin C leads to the disease scurvy due to the role of the vitamin in the post-translational modification of collagens. Scurvy is characterized by easily bruised skin, muscle fatigue, soft swollen gums, decreased wound healing and hemorrhaging, osteoporosis, and anemia. Vitamin C is readily absorbed and so the primary cause of vitamin C deficiency is poor diet and/or an increased requirement. The primary physiological state leading to an ihcreased requirement for vitamin C is severe stress (or trauma). This is due to a rapid depletion in the adrenal stores of the vitamin. The reason for the decrease in adrenal vitamin C levels is unclear but may be due either to redistribution of the vitamin to areas that need it or an overall increased utilization. 

Kivirikko, K I, Myllyla, R, Post-translational modifications. In Collagen in Health and Disease, Weiss, J B, and Jayson, M I V, Eds., Churchill Livingstone, Edinburgh, pp. 101-120, 1982. 

Several other types of covalent crosslinks, mostly derived from lysine or 5-hydroxylysine residues (the latter being formed by post-translational modification), are found in collagen and elastin. A few examples are given (5.2-5.7) A6 7-dehy-drolysinonorleucine (5.2), lysinonorleucine (5.3), dehydrohydroxylysinonorleucine (5.4), lysino-5-ketonorleucine (5.5), desmosine (5.6) and isodesmosine (5.7). An intrachain thiol ester loop is present in a2-macroglobulin and proteins of the complement system and consists of a fifteen-membered ring derived from cysteine and glutamic acid (5.8). 

The spatial variation of crosslinks at bone-forming trabecular surfaces (within 50 gm) in patients with osteoporotic or multiple spontaneous fractures was significantly different from that in normal bone, and the collagen crosslink ratio was higher. It has been hypothesized that the matrix produced in osteoporosis might mature more quickly or undergo post-translational modifications for a longer time than normal bone matrix. 

Hydroxyamino acids are useful because the OH group can be converted into a leaving group. We saw serine 138 earlier in the chapter. The other three have a secondary alcohol at a potentially useful chiral centre. Threonine 347 is found in normal proteins. The other two are present in collagen and the extra hydroxyl groups are added by oxidation after the protein is formed ( post-translational modification ). Hydroxyproline 331 is abundant, hydroxylysine 330 less so. We might also add synthetic phenylglycine as a new member. 

Explain the role of ascorbate (Vitamin C) in collagen formation. Outline the post-translational modification of proline to hydroxy proline. 

Early in our studies it was expected that the post-translational modification of proline hydroxylation, so important to proper collagen structure and function, would raise the value of the temperature, T, for the onset of the inverse temperature transition for models of elastin. Accordingly, hydroxyproline (Hyp) was incorporated by chemical synthesis into the basic repeating sequence to give the protein-based polymers poly[fvs,i(Val-Pro-Gly-Val-Gly), fHyp( al-Hyp-Gly-Val-Gly)], where f sl -i- fnyp = 1 and values of fnyp were 0, 0.01, and 0.1. The effect of prolyl hydroxylation is shown in Figure 7.49. Replacement of proline by hydroxyproline markedly raises the temperature for hydrophobic association. Prolyl hydroxylation moves the movable cusp of... 

The majority of data on the biosynthesis and catabolism of collagens has been derived from studies on the most abundant, interstitial collagens, particularly type I collagen, but it is generally beheved that most processes will be common to all collagen types (30). Overall, it is a complex process, being similar to the pattern of assembly of other multisubunit proteins, but is characterized by the involvement of a large number of specific intracellular and extracellular post-translational modification reactions (Fig. 4). 

Bank, R.A. et al.. Ageing and zonal variation in post-translational modification of collagen in normal human articular cartilage. The age-related increase in non-enzymatic glycation affects biomechanical properties of cartilage. Biochem J, 1998. 330(Pt 1) 345-51. 

Composition and The amino acid composition of collagen is quite distinctive. Nearly one-third of post-translational its residues are Gly, while another one-quarter are Pro, significantly higher modifications proportions than are found in other proteins. The hydroxylated amino acids... 

Figure 12. Proposed scheme for in vivo post-translational enzymatic modifications involved in collagen formation (adapted from Refs. 78, 79,...

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