Biochemistry of Collagens, Laminins and Elastin

Structure, Function and Biomarkers

Morten Karsdal

• Editorial: Academic Press
• Año: 2019
• ISBN:
  9780128170694
• Edición: 2
• Categoría: Biological Sciences
• Categoría: Biophysics

There are 28 different collagens, with 46 unique chains, which allows for a collagen for each time and place. Some collagens are specialized for basement membrane, whereas others are the central structural component of the interstitial matrix. There are eight collagens among the 20 most abundant proteins in the body, which makes these molecules essential building blocks of tissues. In addition, lessons learned from monogenomic mutations in these proteins result in grave pathologies, exemplifying their importance in development. These molecules, and their post-translationally modified products serve as biomarkers of diseases in a range of pathologies associated with the extracellular matrix.

Biochemistry of Collagens, Laminins, and Elastin: Structure, Function, and Biomarkers, Second Edition provides researchers and students current data on key structural proteins (collagens, laminins, and elastin), reviews on how these molecules affect pathologies, and information on how selected modifications of proteins can result in altered signaling properties of the original extracellular matrix component. Further, it discusses the novel concept that an increasing number of components of the extracellular matrix harbor cryptic signaling functions that may be viewed as endocrine function, and it highlights how this knowledge can be exploited to modulate fibrotic disease.

• Provides an updated comprehensive introduction to collagen and structural proteins
• Gives insight into emerging analytical technologies that can detect biomarkers of extracellular matrix degradation
• Includes seven new chapters, including one on how collagen biomarkers are used in clinical research to support drug development and in precision medicine
• Contains insights into the biochemical interactions and changes to structural composition of proteins in disease states
• Proves the importance of proteins for collagen assembly, function, and durability

Chapter 1

Type I collagen

K. Henriksen, and M.A. Karsdal Nordic Bioscience, Herlev, Denmark

Keywords

Biomarkers; Bone; Crosslinks; Osteogenesis imperfecta; Prediction; Type I collagen

1. References

Summary

Type I collagen is one of the most abundant molecules in the body, and it is particularly important in bone, skin, and connective tissue. It is an interstitial matrix collagen organized in fibrils, which are essential for the competence of several tissues, including bone and skin, as illustrated by the observation of osteogenesis imperfecta and Ehlers–Danlos syndrome in subjects with mutations in type I collagen. Type I collagen has a host of posttranslational modifications, some formed during synthesis to ensure mechanical competence of the fibrils, such as interhelical and interfibrillar crosslinks, and some formed as a function of aging and disease, such as cleavage and glycation, and often resulting in reduced competence of the fibrils. Biomarkers of both type I collagen synthesis and degradation have proven of great utility, particularly in the osteoporosis field, where the discovery of the cathepsin K-generated fragment CTX revolutionized the field, but also in other fields where MMP-generated fragments are now being utilized to monitor antiinflammatory responses.

Type I collagen is the most abundant collagen, and is expressed in virtually all connective tissues. It is an interstitial matrix component and the major structural protein of bone, skin, tendon, ligament, sclera, cornea, blood vessels, as well as an important component of other tissues. Of these tissues, bone and skin are the organs with the most prominent functional role for type I collagen. Type I collagen comprises approximately 95% of the entire collagen content of bone and about 80% of the total proteins present in bone [1], thereby representing the tissue with, by far, the largest amount of type I collagen.

The genes encoding type I collagen are COL1A1 and COL1A2 (Table 1.1), and their importance is underlined by genetic studies showing that mutations in the these genes can lead to osteogenesis imperfecta, Ehlers–Danlos syndrome, or Caffey disease (Table 1.1 and Chapter 32) [2].

Table 1.1

Overview of type I collagen.

Type I collagen	Description	References
Gene name and number	COL1A1, location 17q21.3-q22 COL1A2, location 7q21.3-22.1	Gene ID 1277 Gene ID 1278
Mutations with diseases in man	Osteogenesis imperfecta I–IV Ehlers-Danlos Caffey disease	[55–59]
Tissue distribution in healthy states	Ubiquitous	[1]
Tissue distribution in pathological affected states	Ubiquitous	[1]
Special domains	Like other fibrillar collagens it consist of three NC domains (1–3) + two Col domains (1–2)	[3,4]
Special neoepitopes	N- and C-terminal propeptides, and N- and C-terminal degradation peptides	[3,4]
Protein structure and function	Type I collagen is a heterotrimer molecule in most cases composed of two α1 chains and one α2 chain, albeit an α1 homotrimer exists as a minor form. Each chain consists of more than 1000 amino acids, glycines at every third position of the helical domain are crucial for the helix Essential component for the mechanical competence of the bone extracellular matrix, but also a key structural component of many other tissues. Full function not yet clear	[3,4] [7,9,60–62]
Binding proteins	Integrins, proteoglycans, and many more	[7,9]
Known central function	The main organic component of bone, indispensable for bone integrity	[7,9]
Animals models	COL1A2-deficient mice (oim mice), collagenase-resistant collagen I mouse	[3,4]
Biomarkers	Alpha and beta-CTX-1, NTX, ICTP, PINP, PICP, C1M	[25,26]

C1M, type I collagen neo-epitope; COL, Collagen; CTX-I, C-terminal crosslinked telopeptide of type I collagen; ICTP, type I collagen-derived crosslinked carboxyterminal telopeptide; NTX, N-terminal crosslinked telopeptide of type I collagen; PICP, carboxy-terminal propeptide of procollagen type I; PINP, amino-terminal propeptide of procollagen type I.

Figure 1.1 Schematic illustration of the primary structure of type I collagen including depiction of the functional domains.

Figure 1.2 Tertiary structure of type I collagen.

Biosynthesis of type I collagen follows a rather general route, involving propeptide removal and the formation of lysyl-crosslinks, as described in the introduction.

In general, type I collagen molecules consist of heterotrimers made up from two α1 chains and one α2 chain, but a low level of α1 homotrimers has also been reported. The full-length type I collagen is around 300 nm long and has a width of 1–5 nm, while each individual collagen chain is built from more than 1000 amino acids.

Type I collagen has three major domains: an N-terminal nontriple helical domain (N-telopeptide), a central triple helical domain, and a C-terminal nontriple helical domain (C-telopeptide), and the central domain comprises approximately 95% of the total molecule [3]. The unique (to collagens) triple helical domain is permitted by the presence of numerous glycine-X-Y repeats, where X often is a proline and Y is a hydroxyproline, resulting in repeated kinks in the sequence allowing the helical structure. Glycine at every third position is essential for the correct formation of the structure, as clearly underlined by the large number of mutations in these glycines resulting in osteogenesis imperfecta Fig. 1.1 [3].

The type I collagen molecules are extensively modified at the posttranslational level, including the removal of the N- and C-terminal propeptides through enzymatic cleavage, and the formation of lysyl-crosslinks all modifications, which are essential for the correct structural conformation of the triple helix, and the mechanical competence of the assembled collagen fibrils Fig. 1.2 [3]. A series of other posttranslational modifications (PTMs), including isomerization, racemization, enzymatic cleavage, glycosylation, and glycation, arise as a function of biological changes and have proven to be highly relevant, not just from the biological point of view, but also as biomarkers of different disease aspects (see discussion on biomarkers later in this chapter) [4,5].

The accumulation of posttranslational modifications during synthesis and formation of the collagen fibrils was extensively reviewed recently [3,6], and hence a thorough description of this is beyond the scope of this chapter. Briefly, a series of prolyl hydroxylase-mediated hydroxylations of the prolines in position Y of the G-X-Y repeats occur. In ad...

Índice

• Cover image
• Title page
• Table of Contents
• Copyright
• List of contributors
• Foreword
• Preface
• Acknowledgments
• List of abbreviations
• Introduction
• Chapter 1. Type I collagen
• Chapter 2. Type II collagen
• Chapter 3. Type III collagen
• Chapter 4. Type IV collagen
• Chapter 5. Type V collagen
• Chapter 6. Type VI collagen
• Chapter 7. Type VII collagen
• Chapter 8. Type VIII collagen
• Chapter 9. Type IX collagen
• Chapter 10. Type X collagen
• Chapter 11. Type XI collagen
• Chapter 12. Type XII collagen
• Chapter 13. Type XIII collagen
• Chapter 14. Type XIV collagen
• Chapter 15. Type XV collagen
• Chapter 16. Type XVI collagen
• Chapter 17. Type XVII collagen
• Chapter 18. Type XVIII collagen
• Chapter 19. Type XIX collagen
• Chapter 20. Type XX collagen
• Chapter 21. Type XXI collagen
• Chapter 22. Type XXII collagen
• Chapter 23. Type XXIII collagen
• Chapter 24. Type XXIV collagen
• Chapter 25. Type XXV collagen
• Chapter 26. Type XXVI collagen
• Chapter 27. Type XXVII collagen
• Chapter 28. Type XXVIII collagen
• Chapter 29. Laminins
• Chapter 30. Elastin
• Chapter 31. The collagen chaperones
• Chapter 32. Collagen diseases
• Chapter 33. The signals of the extracellular matrix
• Chapter 34. The roles of collagens in cancer
• Chapter 35. Use of extracellular matrix biomarkers in clinical research
• Chapter 36. Common confounders when evaluating noninvasive protein biomarkers
• Chapter 37. Implementation of collagen biomarkers in the clinical setting
• Index