Evidence of reciprocal reorientation of the catalytic and hemopexin-like domains of full-length MMP-12

Matrix metalloproteinases (MMP) are an important family of 23 proteins which are involved in a number of extracellular processes including the degradation of the extracellular matrix.1,2 All active MMPs but MMP-7 are constituted by two domains, a catalytic (CAT) and a hemopexin-like (HPX) domain. The CAT and HPX domains are connected by a linker whose length varies from 14 to 68 AA.3,4 For the majority of MMPs the linker is relatively short (14-23 AA) while for MMP-9 and MMP-15, at the other extreme, the intervening residues between the CAT and HPX domains (63 and 68 AA, respectively), constitute a further, highly glycosylated, domain termed OG domain. The CAT domain alone bears full proteolytic activity towards a range of peptides and proteins. However, efficient proteolysis of, for instance, triple helical collagen requires the full-length active protein. For this reason it is often hypothesized that the HPX domain helps the local unwinding of the triple helix, in such a way that a single peptide strand can be accommodated in the active site of the CAT domain and cleaved. It has been also hypothesized that a relative mobility of the HPX domain is necessary for this function. In case of full-length MMP-12 the low resolution crystal structure we collected (Figure 1) was largely sufficient to establish that the structure is less compact, and the relative orientation of the two domains totally different, with respect to the four X