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Essays in Biochemistry Sep 2019The procollagen C-propeptides of the fibrillar collagens play key roles in the intracellular assembly of procollagen molecules from their constituent polypeptides... (Review)
Review
The procollagen C-propeptides of the fibrillar collagens play key roles in the intracellular assembly of procollagen molecules from their constituent polypeptides chains, and in the extracellular assembly of collagen molecules into fibrils. Here we review recent advances in understanding the molecular mechanisms controlling C-propeptide trimerization which have revealed the importance of inter-chain disulphide bonding and a small number of charged amino acids in the stability and specificity of different types of chain association. We also show how the crystal structure of the complex between the C-propeptide trimer of procollagen III and the active fragment of procollagen C-proteinase enhancer-1 leads to a detailed model for accelerating release of the C-propeptides from procollagen by bone morphogenetic protein-1 and related proteinases. We then discuss the effects of disease-related missense mutations in the C-propeptides in relation to the sites of these mutations in the three-dimensional structure. While in general there is a good correlation between disease severity and structure-based predictions, there are notable exceptions, suggesting new interactions involving the C-propeptides yet to be characterized. Mutations affecting proteolytic release of the C-propeptides from procollagen are discussed in detail. Finally, the roles of recently discovered interaction partners for the C-propeptides are considered during fibril assembly and cross-linking.
Topics: Collagen Diseases; Disulfides; Fibrillar Collagens; Humans; Mutation; Peptide Fragments; Procollagen; Protein Multimerization; Protein Structure, Quaternary
PubMed: 31243143
DOI: 10.1042/EBC20180049 -
Advances in Clinical Chemistry 2014The synthesis rates of fibrillar collagens can be assessed in blood by measuring propeptides set free from corresponding procollagens before fiber formation. Type I... (Review)
Review
The synthesis rates of fibrillar collagens can be assessed in blood by measuring propeptides set free from corresponding procollagens before fiber formation. Type I collagen is the major component of the organic matrix of bone, but it is also found in other connective tissues. The serum concentration of the amino-terminal propeptide of type I procollagen, PINP, functions as a measure of type I collagen synthesis during normal bone turnover, but it is also released from bone metastases that involve an osteoblastic component. Type III collagen is a major constituent of soft tissues and the corresponding amino-terminal propeptide, PIIINP, reflects collagen synthesis. Circulating PIIINP tends to be affected by malignomas that grow in the peritoneal cavity or affect bone marrow. Many studies on procollagen markers in cancer have been cross-sectional or demonstrated treatment effects in patient groups. Markers that originate from bone turnover have wide reference intervals, but low biologic variability in individuals. Thus, they appear better suited for monitoring versus diagnostic purposes. There is still definite need for research on the use of procollagen markers in the followup of individual patients undergoing cancer treatment or being monitored after such treatment.
Topics: Bone Remodeling; Humans; Neoplasms; Peptide Fragments; Procollagen
PubMed: 25344986
DOI: 10.1016/b978-0-12-801401-1.00003-7 -
Journal of Cell Science Apr 2005Collagen fibrils in the extracellular matrix allow connective tissues such as tendon, skin and bone to withstand tensile forces. The fibrils are indeterminate in length,... (Review)
Review
Collagen fibrils in the extracellular matrix allow connective tissues such as tendon, skin and bone to withstand tensile forces. The fibrils are indeterminate in length, insoluble and form elaborate three-dimensional arrays that extend over numerous cell lengths. Studies of the molecular basis of collagen fibrillogenesis have provided insight into the trafficking of procollagen (the precursor of collagen) through the cellular secretory pathway, the conversion of procollagen to collagen by the procollagen metalloproteinases, and the directional deposition of fibrils involving the plasma membrane and late secretory pathway. Fibril-associated molecules are targeted to the surface of collagen fibrils, and these molecules play an important role in regulating the diameter and interactions between the fibrils.
Topics: Animals; Extracellular Matrix; Fibrillar Collagens; Humans; Procollagen; Protein Transport
PubMed: 15788652
DOI: 10.1242/jcs.01731 -
Nature Reviews. Disease Primers Jul 2020The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary disorders of connective tissue, with common features including joint hypermobility, soft and... (Review)
Review
The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary disorders of connective tissue, with common features including joint hypermobility, soft and hyperextensible skin, abnormal wound healing and easy bruising. Fourteen different types of EDS are recognized, of which the molecular cause is known for 13 types. These types are caused by variants in 20 different genes, the majority of which encode the fibrillar collagen types I, III and V, modifying or processing enzymes for those proteins, and enzymes that can modify glycosaminoglycan chains of proteoglycans. For the hypermobile type of EDS, the molecular underpinnings remain unknown. As connective tissue is ubiquitously distributed throughout the body, manifestations of the different types of EDS are present, to varying degrees, in virtually every organ system. This can make these disorders particularly challenging to diagnose and manage. Management consists of a care team responsible for surveillance of major and organ-specific complications (for example, arterial aneurysm and dissection), integrated physical medicine and rehabilitation. No specific medical or genetic therapies are available for any type of EDS.
Topics: Ehlers-Danlos Syndrome; Humans; Procollagen
PubMed: 32732924
DOI: 10.1038/s41572-020-0194-9 -
Life Science Alliance May 2022The processing of type I procollagen is essential for fibril formation; however, the steps involved remain controversial. We constructed a live cell imaging system by...
The processing of type I procollagen is essential for fibril formation; however, the steps involved remain controversial. We constructed a live cell imaging system by inserting fluorescent proteins into type I pre-procollagen α1. Based on live imaging and immunostaining, the C-propeptide is intracellularly cleaved at the perinuclear region, including the endoplasmic reticulum, and subsequently accumulates at the upside of the cell. The N-propeptide is also intracellularly cleaved, but is transported with the repeating structure domain of collagen into the extracellular region. This system makes it possible to detect relative increases and decreases in collagen secretion in a high-throughput manner by assaying fluorescence in the culture medium, and revealed that the rate-limiting step for collagen secretion occurs after the synthesis of procollagen. In the present study, we identified a defect in procollagen processing in activated hepatic stellate cells, which secrete aberrant collagen fibrils. The results obtained demonstrated the intracellular processing of type I procollagen, and revealed a link between dysfunctional processing and diseases such as hepatic fibrosis.
Topics: Collagen; Endoplasmic Reticulum; Procollagen
PubMed: 35181633
DOI: 10.26508/lsa.202101060 -
Matrix Biology : Journal of the... Feb 1998Recent advances in the understanding of the molecular recognition events occurring during the assembly of procollagen during biosynthesis have come from the use of a... (Review)
Review
Recent advances in the understanding of the molecular recognition events occurring during the assembly of procollagen during biosynthesis have come from the use of a semi-permeabilized cell-system that reconstitutes the initial steps of chain assembly as they would occur in the endoplasmic reticulum of an intact cell. This has enabled a number of key questions concerning the molecular determinants of procollagen assembly to be addressed. In particular, the recognition events underlying the initial association of individual procollagen chains have been investigated, resulting in the identification of the key residues involved within the C-propeptide of fibrillar collagens. Similarly, the role of inter-chain disulfide bond formation in chain recognition and assembly has been investigated, along with the role of the C-propeptide, C-telopeptide and proline hydroxylation in helix nucleation, alignment and propagation. The results from these studies point to a two-stage recognition event, i.e., association of the chains driven by residues within the C-propeptide followed by nucleation and alignment of the helix driven mainly by sequences present at the C-terminal end of the triple helical domain.
Topics: Amino Acid Sequence; Animals; Humans; Models, Chemical; Molecular Sequence Data; Procollagen; Structure-Activity Relationship
PubMed: 9524357
DOI: 10.1016/s0945-053x(98)90010-5 -
Ciba Foundation Symposium 1988All of the type I collagen in connective tissue is the product of one structural gene for the pro alpha 1(I) chain and another for the pro alpha 2(I) chain of type I... (Review)
Review
All of the type I collagen in connective tissue is the product of one structural gene for the pro alpha 1(I) chain and another for the pro alpha 2(I) chain of type I procollagen. An intriguing question therefore is how the expression of the two genes differs in mineralizing and non-mineralizing tissues. One approach that our laboratory has pursued to answer this and related questions is to develop a new system whereby one can examine the self-assembly of collagen fibrils de novo by controlled enzymic cleavage of procollagen to collagen under physiological conditions. The system has made it possible for the first time to define thermodynamic parameters for the self-assembly process. We are now using the system to define the normal kinetics for fibril formation. The results should make it possible to study the effects of other components of extracellular matrix on fibril assembly, including the effects of bone-specific components that initiate mineralization. A second approach has been to define mutations in type I procollagen genes that cause increased brittleness of bone. Over a dozen mutations in type I procollagen genes have been found in probands with osteogenesis imperfecta. One of the surprises has been that at least 25% of the probands with lethal variants of osteogenesis imperfecta have mutations in type I procollagen genes. Another surprise has been the observation that a number of the mutations are tissue specific in terms of their phenotypic manifestations even though the same abnormal pro alpha chains are being synthesized in a variety of tissues.
Topics: Amino Acid Sequence; Animals; Base Sequence; Bone Diseases; Collagen; Genes; Humans; Molecular Sequence Data; Mutation; Procollagen
PubMed: 3068007
DOI: 10.1002/9780470513637.ch10 -
American Journal of Medical Genetics Sep 1989Recent data from several laboratories have established that most variants of osteogenesis imperfecta (OI) are caused by mutations in the 2 structural genes for type I... (Review)
Review
Type I procollagen: the gene-protein system that harbors most of the mutations causing osteogenesis imperfecta and probably more common heritable disorders of connective tissue.
Recent data from several laboratories have established that most variants of osteogenesis imperfecta (OI) are caused by mutations in the 2 structural genes for type I procollagen. There are 2 general reasons for the large number of mutations in type I procollagen in OI. One reason is that most of the structure of the procollagen monomer is essential for normal biological function of the protein. The second reason is that most of the mutations cause synthesis of structurally altered pro alpha chains of type I procollagen. The deleterious effects of the structurally altered pro alpha chains are then amplified by at least 3 mechanisms. One mechanism is a phenomenon referred to as "procollagen suicide" whereby altered pro alpha chains cause degradation of normal pro alpha chains synthesized by the same cell. Another mechanism involves the fact that many of the structurally altered pro alpha chains prevent normal processing of the N-propeptides of procollagen and persistence of the N-propeptide interferes with normal fibril assembly. A third mechanism is a recently discovered phenomenon in which a substitution of a bulkier amino acid for glycine can cause a kink in the triple helix of the molecule. The kinked collagen, in turn, causes formation of abnormally branched fibrils. Because the deleterious effects of abnormal pro alpha chains are amplified by these 3 mechanisms, most of the mutations are dominant and many are dominant lethal. The conclusion that most variants of OI are caused by mutations in the structural genes for type I procollagen has broad implications for other diseases that affect connective tissue, diseases such as chondrodystrophies, osteoarthritis, and osteoporosis.
Topics: Amino Acid Sequence; Base Sequence; Connective Tissue Diseases; Humans; Molecular Sequence Data; Mutation; Osteogenesis Imperfecta; Procollagen
PubMed: 2683782
DOI: 10.1002/ajmg.1320340112 -
Biochimica Et Biophysica Acta Nov 2013Extracellular matrix (ECM) proteins create structural frameworks in tissues such as bone, skin, tendon and cartilage etc. These connective tissues play important roles... (Review)
Review
Extracellular matrix (ECM) proteins create structural frameworks in tissues such as bone, skin, tendon and cartilage etc. These connective tissues play important roles in the development and homeostasis of organs. Collagen is the most abundant ECM protein and represents one third of all proteins in humans. The biosynthesis of ECM proteins occurs in the rough endoplasmic reticulum (rER). This review describes the current understanding of the biosynthesis and folding of procollagens, which are the precursor molecules of collagens, in the rER. Multiple folding enzymes and molecular chaperones are required for procollagen to establish specific posttranslational modifications, and facilitate folding and transport to the cell surface. Thus, this molecular ensemble in the rER contributes to ECM maturation and to the development and homeostasis of tissues. Mutations in this ensemble are likely candidates for connective tissue disorders. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.
Topics: Animals; Endoplasmic Reticulum, Rough; Extracellular Matrix Proteins; Humans; Molecular Chaperones; Procollagen
PubMed: 23602968
DOI: 10.1016/j.bbamcr.2013.04.008 -
Seminars in Cell & Developmental Biology Oct 1999Procollagen assembly occurs within the endoplasmic reticulum, where the C-propeptide domains of three polypeptide alpha-chains fold individually, and then interact and... (Review)
Review
Procollagen assembly occurs within the endoplasmic reticulum, where the C-propeptide domains of three polypeptide alpha-chains fold individually, and then interact and trimerise to initiate folding of the triple helical region. This highly complex folding and assembly pathway requires the co-ordinated action of a large number of endoplasmic reticulum-resident enzymes and molecular chaperones. Disease-causing mutations in the procollagens disturb folding and assembly and lead to prolonged interactions with molecular chaperones, retention in the endoplasmic reticulum, and intracellular degradation. This review focuses predominantly on prolyl 1-hydroxylase, an essential collagen modifying enzyme, and HSP47, a collagen-specific binding protein, and their proposed roles as molecular chaperones involved in fibrillar procollagen folding and assembly, quality control, and secretion.
Topics: Collagen; Endoplasmic Reticulum; Gene Expression Regulation; HSP47 Heat-Shock Proteins; Heat-Shock Proteins; Humans; Molecular Chaperones; Osteogenesis Imperfecta; Procollagen; Procollagen-Proline Dioxygenase; Protein Binding; Protein Folding
PubMed: 10597628
DOI: 10.1006/scdb.1999.0317