The Pro-α3(V) Collagen Chain

Abstract

The low abundance fibrillar collagen type V is widely distributed in tissues as an ␣1(V) 2 ␣2(V) heterotrimer that helps regulate the diameters of fibrils of the abundant collagen type I. Mutations in the ␣1(V) and ␣2(V) chain genes have been identified in some cases of classical Ehlers-Danlos syndrome (EDS), in which aberrant collagen fibrils are associated with connective tissue fragility, particularly in skin and joints. Type V collagen also exists as an ␣1(V)␣2(V)␣3(V) heterotrimer that has remained poorly characterized chiefly due to inability to obtain the complete primary structure or nucleic acid probes for the ␣3(V) chain or its biosynthetic precursor, pro-␣3(V). Here we provide human and mouse fulllength pro-␣3(V) sequences. Pro-␣3(V) is shown to be closely related to the ␣1(V) precursor, pro-␣1(V), but with marked differences in N-propeptide sequences, and collagenous domain features that provide insights into the low melting temperature of ␣1(V)␣2(V)␣3(V) heterotrimers, lack of heparin binding by ␣3(V) chains and the possibility that ␣1(V)␣2(V)␣3(V) heterotrimers are incorporated into heterotypic fibrils. In situ hybridization of mouse embryos detects ␣3(V) expression primarily in the epimysial sheaths of developing muscles and within nascent ligaments adjacent to forming bones and in joints. This distribution, and the association of ␣1(V), ␣2(V), and ␣3(V) chains in heterotrimers, suggests the human ␣3(V) gene COL5A3 as a candidate locus for at least some cases of classical EDS in which the ␣1(V) and ␣2(V) genes have been excluded, and for at least some cases of the hypermobility type of EDS, a condition marked by gross joint laxity and chronic musculoskeletal pain. COL5A3 is mapped to 19p13.2 near a polymorphic marker that should be useful in analyzing linkage with EDS and other disease phenotypes.Monomers of the low abundance fibrillar collagen types V and XI are incorporated into fibrils of the abundant collagen types I and II, respectively (1, 2). In vitro fibrillogenesis experiments (3, 4) and analysis of a type V mutation in transgenic mice (5) have indicated that type V collagen helps regulate the size and shape of type I/V heterotypic fibrils. Further evidence that type V collagen plays a role in regulating type I collagen fibrillogenesis in vivo comes from the heritable connective tissue disorder classical Ehlers-Danlos syndrome (EDS), 1 in which type I collagen fibrils of abnormal shape and diameter have been shown to result from mutations in type V collagen genes (6 -10). Similar evidence for an in vivo role for type XI collagen in regulating type II collagen fibrillogenesis comes from a study of chondrodysplasia, in which abnormal type II collagen fibrils were shown to result from defects in a type XI collagen gene (11).Type V collagen is widely distributed in vertebrate tissues as an ␣1(V) 2 ␣2(V) heterotrimer (12, 13). However, other forms of type V collagen include an ␣1(V) 3 homotrimer that is secreted by a line of Chinese hamster cells (14) and which may also exist in normal tissues...

Biosynthetic Processing of the Pro-α1(V)2Pro-α2(V) Collagen Heterotrimer by Bone Morphogenetic Protein-1 and Furin-like Proprotein Convertases

“…Conservation of sequences suitable for cleavage by furin-like proteases within C-telopeptide regions of pro-␣1(V), pro-␣3(V), pro-␣1(XI), and pro-␣2(XI) chains (39,56) suggests C-propeptides of this subset of fibrillar procollagen chains to be cleaved by furin-like enzymes. This proposed similarity in processing fits the observation that these chains form a subgroup among fibrillar procollagen chains on the basis of sequence similarities, structures of cognate genes, and size and configuration of N-propeptides (56,57). However, although residues at the P 1 Ј, P 3 Ј, and P 2 positions of the pro-␣1(V) chain N-propeptide BMP-1 cleavage site are conserved at the same positions in pro-␣1(XI) and pro-…”

“…Although Kessler et al (40) suggest that pro-␣1(V) C-propeptides may be cleaved by BMP-1-like enzymes in some cells and furin-like enzymes in others, this seems unlikely, as various furin-like proteases are broadly expressed and furin itself, a major processing enzyme of the constitutive secretory pathway, is expressed in all tissues and cell lines examined to date (54,55). Conservation of sequences suitable for cleavage by furin-like proteases within C-telopeptide regions of pro-␣1(V), pro-␣3(V), pro-␣1(XI), and pro-␣2(XI) chains (39,56) suggests C-propeptides of this subset of fibrillar procollagen chains to be cleaved by furin-like enzymes. This proposed similarity in processing fits the observation that these chains form a subgroup among fibrillar procollagen chains on the basis of sequence similarities, structures of cognate genes, and size and configuration of N-propeptides (56,57).…”

Typ 5-Kollagen im Gelenkknorpel von Mensch und Pferd

“…Identification of the cells expressing the mRNAs for these collagens supports the immunohistochemical observations. Type V collagen mRNAs, α1(V) and α3(V), are expressed by cells lining developing joint cavities, presumably putative articular chondrocytes, but not by epiphyseal chondrocytes of 15.5 and 16.5 day fetal mice, whereas type XI collagen mRNAs, α1(XI) and α2(XI), are expressed only by epiphyseal chondrocytes of 15.5-day fetuses (Andrikopoulis et al 1992, Sugimoto et al 1998, Imamura et al 2000.…”

The Transcription Factor CCAAT-binding Factor CBF/NF-Y and Two Repressors Regulate the Core Promoter of the Human Pro-α3(V) Collagen Gene (COL5A3)

“…Recently, human and mouse full-length pro-␣3(V) sequences were provided (16). These were shown to be closely related to the pro-␣1(V) chain.…”

“…Recently, a fourth chain, ␣4(V), expressed in rat Schwann cells was reported (15). This ␣ chain, which can form molecules with ␣1(V) and ␣2(V) chains, seems to be the counterpart of the mouse and human ␣3(V) chain (16).…”