Metalloproteases meprin α and meprin β are C- and N-procollagen proteinases important for collagen assembly and tensile strength.
Type I fibrillar collagen is the most abundant protein in the human body, crucial for the formation and strength of bones, skin, and tendon. Proteolytic enzymes are essential for initiation of the assembly of collagen fibrils by cleaving off the propeptides. We report that Mep1a(-/-) and Mep1b(-/-) mice revealed lower amounts of mature collagen I compared with WT mice and exhibited significantly reduced collagen deposition in skin, along with markedly decreased tissue tensile strength. While exploring the mechanism of this phenotype, we found that cleavage of full-length human procollagen I heterotrimers by either meprin α or meprin β led to the generation of mature collagen molecules that spontaneously assembled into collagen fibrils. Thus, meprin α and meprin β are unique in their ability to process and release both C- and N-propeptides from type I procollagen in vitro and in vivo and contribute to the integrity of connective tissue in skin, with consequent implications for inherited connective tissue disorders.
Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
Claudia
C
Broder
Philipp
P
Arnold
Sandrine
S
Vadon-Le Goff
Moritz A
MA
Konerding
Kerstin
K
Bahr
Stefan
S
Müller
Christopher M
CM
Overall
Judith S
JS
Bond
Tomas
T
Koudelka
Andreas
A
Tholey
David J S
DJ
Hulmes
Catherine
C
Moali
Christoph
C
Becker-Pauly
D000818:Animals; D016466:CHO Cells; D024042:Collagen Type I / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011348:Procollagen N-Endopeptidase / Q000378:metabolism*; D059748:Proteolysis; D012867:Skin / Q000378:metabolism; D013718:Tensile Strength
D024042:Collagen Type I; D008666:Metalloendopeptidases; D011348:Procollagen N-Endopeptidase; C053833:meprin A; C095663:meprin B
Ehlers–Danlos syndrome; connective tissue; fibrosis; proteolysis; proteomics