Mutations in matrilin-3 have been associated with common skeletal diseases like osteoarthritis as well as with the rare chondrodysplasias MED and SEMD. We have previously shown that the mutations p.R116W and p.C299S, associated with MED and SEMD, respectively, cause retention of matrilin-3 within the endoplasmic reticulum of primary chondrocytes, while the mutation associated with osteoarthritis, p.T298M, does not hinder secretion. The present study focused on the consequences of the p.T298M mutation on the structure of matrilin-3 and on the role of matrilin-3 in the formation of a functional extracellular matrix. Analysis of recombinant full-length matrilin-3 revealed that the p.T298M mutation does not influence oligomerization of matrilin-3 or its proteolytic processing by ADAMTS-4 and -5. Nevertheless, structural analyses indicate local conformational changes. These changes do not affect the affinity for collagens II, IX, XI, or COMP, but have a major impact on the in vitro fibrillogenesis of collagen II/IX/XI heterofibrils.
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