The matrilins: a novel family of oligomeric extracellular matrix proteins
Introduction
The fact that the matrilins form a protein family has emerged only in recent years with the discoveries of matrilins-2 (Deák et al., 1997), -3 (Belluoccio and Trueb, 1997; Wagener et al., 1997) and -4 (Wagener et al., 1998a). The prototype member of this family is matrilin-1, which was earlier referred to as cartilage matrix protein (CMP) as it was initially identified as an abundant, proteoglycan-associated protein present in many forms of cartilage (Paulsson and Heinegård, 1979, Paulsson and Heinegård, 1981, Paulsson and Heinegård, 1982). Determination of the primary structure of matrilin-1 showed it to be a modular protein consisting of two von Willebrand Factor A (vWFA) domains, connected by a single epidermal growth factor (EGF)-like domain, followed by a C-terminal module that displays a heptad repeat and allows the assembly of the subunits by forming a triple-coiled coil (Argraves et al., 1987; Kiss et al., 1989; Hauser and Paulsson, 1994). The matrilins are now defined as modular proteins containing the same domains in the same order as in matrilin-1.
Section snippets
Structure
The domain structures of the matrilins are given in a schematic form in Fig. 1. The vWFA domains fall into two groups with the vWFA1 module always occuring towards the N-terminus and the vWFA2 module closer to the C-terminus. In matrilin-3 the vWFA2 module and in one splice variant of mouse matrilin-4 the vWFA1 module has been deleted. vWFA domains are found not only in the matrilins, but also in a large number of other extracellular proteins such as von Willebrand factor, collagens type VI,
Evolution
All known matrilins appear to originate from a common ancestor. This conclusion is based mainly on two observations. First, all matrilins contain the same modules in the same order. Second, all modules are more closely related to the corresponding modules of other matrilins, than to any other proteins. This is particularly true for the vWFA modules both at the DNA and protein level though the same relationship was observed within the EGF module superfamily. The similarity of the coiled coil
Supramolecular assembly
The exact assembly forms of matrilins in the extracellular matrix are largely unknown even though some information is available for matrilin-1. This protein was first identified because of its tight association with aggrecan, which resulted in a copurification of matrilin-1 and aggrecan (Paulsson and Heinegård, 1979). Some molecules of matrilin-1 even become covalently bound to the aggrecan core protein and can by electron microscopy be detected as globular particles attached at distinct sites
Gene structure and expression
A single copy gene, which consists of eight exons and has a conserved structure, has been reported for chicken, human and mouse matrilin-1 (Kiss et al., 1989; Jenkins et al., 1990; Aszódi et al., 1998). The human and the mouse genes are located on chromosome 1p35 and on the distal part of chromosome 4 between markers D4Mit16 and D4Mit339, respectively (Jenkins et al., 1990; Aszódi et al., 1998). The human matrilin-4 gene consists of 10 exons (Wagener et al., 1998b) and a matrilin-4 EST has been
Control of matrilin-1 gene expression
The expression patterns of the various matrilin genes suggest that the regulation of matrilin-1 and -3 genes may involve control mechanisms similar to each other as well as to other cartilage protein genes, while the matrilin-2 gene is regulated by entirely independent mechanisms. To date, information on the transcriptional control is available only for the chicken matrilin-1 gene. The gene is transcribed from two initiation sites located 31 and 39 bp downstream of a TATA-like promoter (Kiss et
Pathology
So far the matrilin genes have not been found linked to congenital disorders of development. The matrilin-1 gene is mapped close to the achondroplasia (cn) locus, but detailed analysis revealed that the matrilin-1 gene is not mutated in cn/cn mice (Aszódi et al., 1998). It has further been excluded as the mutant locus in several heritable human chondrodysplasias (Loughlin et al., 1994a) as well as in generalised osteoarthritis (Loughlin et al., 1994b). Matrilin-1 concentrations in serum are
Acknowledgements
Our work on matrilins is supported by grants from the Hungarian National Scientific Research Foundation (OTKA T022224 and T023803), joint grants from the Volkswagen-Stiftung (I/71 654) and the bilateral German-Hungarian cooperation programme (WTZ), grants from the Deutsche Forschungsgemeinschaft (Pa 660/1-1 and Kr 558/10-3) and from the Köln Fortune programme of the Medical Faculty of the University of Cologne. We are grateful to all our friends and colleagues who have contributed to our
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