The
von Willebrand Factor A (vWF A) domain is one of the most widely distributed structural modules in cell-matrix adhesive molecules such as intergrins and
extracellular matrix proteins. Mutations in the vWF A domain of
matrilin-3 cause
multiple epiphyseal dysplasia (MED), however the pathological mechanism remains to be determined. Previously we showed that the vWF A domain in
matrilin-1 mediates formation of a filamentous matrix network through
metal-ion dependent adhesion sites in the domain. Here we show two new functions of the vWF A domain in cartilage-specific
matrilins (1 and 3). First, vWF A domain regulates oligomerization of
matrilins. Insertion of a vWF A domain into
matrilin-3 converts the formation of a mixture of
matrilin-3 tetramer, trimer, and dimer into a tetramer only, while deletion of a vWF A domain from
matrilin-1 converts the formation of the native
matrilin-1 trimer into a mixture of trimer and dimer. Second, the vWF A domain protects
matrilin-1 from proteolysis. We identified a latent proteolytic site next to the vWF A2 domain in
matrilin-1, which is sensitive to the inhibitors of matrix
proteases. Deletion of the abutting vWF A domain results in degradation of
matrilin-1, presumably by exposing the adjacent proteolytic site. In addition, we also confirmed the vWF A domain is vital for the secretion of
matrilin-3. Secretion of the mutant
matrilin-3 harbouring a point mutation within the vWF A domain, as occurred in MED patients, is markedly reduced and delayed, resulting from intracellular retention of the mutant
matrilin-3. Taken together, our data suggest that different mutations/deletions of the vWF A domain in
matrilins may lead to distinct pathological mechanisms due to the multiple functions of the vWF A domain.