The Link Module Superfamily

The human Link module superfamily currently has 14 members and the majority of these contain a variety of other domain types (Fig. 2). Previously we have suggested (8) that this superfamily can be divided into three subgroups according to the known or expected size of their HA-binding domains (HABDs) (see Fig. 3). Type A domains are comprised of a single, independently folding Link module, as found in TSG-6 (13,14). The proteins KIA0527, Stabilin-1 and Stabilin-2, which all contain a single Link module (Fig. 2), could also belong to this subgroup. Type B domains, however, require N- and C-terminal extensions flanking the Link module for correct folding and functional activity, and these are typified by the ~150 amino acid HABD of CD44 (15); the HA receptor found on lymph vessel endothelium (i.e., LYVE-1) may also have a HABD of this type. The third class of HABD (Type C) is comprised of a contiguous pair of Link modules, which in some cases may also require an N-terminal immunoglobulin module for fold stabilisation. Type C domains are found in the G1-domains of the chondroitin sulphate proteoglycans (CSPGs) aggrecan, versican, neurocan and brevican, and in the HAPLN proteins."/>
Figure 2 The mosaic nature of the Link module superfamily. The symbols depicting the various modules and the domain organisations are derived from the SMART database (

A. HAPLN Proteins and CSPGs

The Link module was first identified in cartilage link protein isolated from rat chondrosarcoma (16). Recently a link protein gene family consisting of four members has been identified (17) and denoted 'HAPLN' (HA and Proteoglycan LiNk protein family). In this new nomenclature, cartilage link protein corresponds to HAPLN-1, and the gene product of BRAL1 (Brain Link Protein 1 (18)) is renamed HAPLN-2. Interestingly, in the vertebrate genome the four HAPLN genes were all found to be located immediately adjacent to one of the four CSPG genes, i.e., forming HAPLN-1/versican, HAPLN-2/brevican, HAPLN-3/aggrecan and HPLN-4/neurocan gene pairs (17). While brain-specific HAPLN-2 and HAPLN-4 were co-expressed with the two brain-specific CSPGs

Figure 3 The Link module superfamily can be divided into three subgroups on the basis of domain size. The tertiary structures for Type A and B HA-binding domains have been determined from TSG-6 and CD44, respectively (see text). To date, there are no structural data for Type C domains.

(brevican and neurocan), the expression profiles for HAPLN-1 and 3 did not match their corresponding gene partner. For example, HAPLN-1 is mainly restricted to cartilage, where it associates cooperatively with the CSPG aggrecan forming stable complexes with HA (19), while versican is more widely expressed.

The four encoded HAPLN proteins share 45-52% overall amino acid identity, where the highest degree of similarity is in the Link module domains (17). At present the specificity of HAPLN-CSPG interactions is not known. It would seem likely that both HAPLN-2 and 4 form 'link protein'-stabilised complexes with neurocan and/or brevican, given their common tissue expression. However, HAPLN-2 has been reported to co-localise with the V2 splice variant of versican in the brain (20), revealing the possibility that a particular HAPLN protein may associate with more than one CSPG. Clearly, much further work is needed to clarify this question.

The interaction between HAPLN-1 and aggrecan is believed to be mediated via the association of their N-terminal immunoglobulin domains (21-23). However, a recent paper (23) reports that versican also interacts with HAPLN-1, but in this case via its Link module domains. This might indicate that there is considerable complexity in the details of link protein/CSPG interactions leading to aggregates with HA of diverse quaternary structure.

All four HAPLN proteins are predicted to interact with HA based on analyses of their Link module sequences, and these have many features in common with cartilage link protein and the well-characterised hyaladherin TSG-6 (14,17,24). In aggrecan and HAPLN-1, both Link modules in the Type C domains are known to be involved in the interaction with HA (22,25). However, to date there are no structural data for any of these proteins, so that the exact way in which the two Link modules dock together to form a Type C HA-interaction domain is not clear.

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