Cleavage of the carboxyl tail from the G3 domain of aggrecan but not versican and identification of the amino acids involved in the degradation.

The Journal of Biological Chemistry
Vivian LeeBurton B Yang

Abstract

Aggrecan, a major structural proteoglycan in cartilage, contains three globular domains, G1, G2, and G3, as well as sequences for glycosaminoglycan modification. A large number of proteases are implicated in aggrecan cleavage in normal metabolism, aging, and arthritis. These proteases are known to cleave at the IGD, KS, and CS domains. Here we report for the first time evidence of cleavage at a novel site, the carboxyl tail of aggrecan. Results from deletion mutants of the tail indicated that the likely cleavage sites were two consensus sequences, RRLXK and RSPR, present in the aggrecan analogs of many species. This was confirmed by site-directed mutagenesis. A construct containing two G3 domains (G3G3) was also found to cleave between the G3 duplicates. When G3 tail was linked to a glycosaminoglycan-modifying sequence, it was protected from cleavage. Furin inhibitor also reduced the levels of tail cleavage. The carboxyl tails of chicken and human versican were not cleaved, despite the presence of the consensus sequence. Our studies indicate that the basic amino acids present in the tail play an important role in cleavage, and this mechanism is specific to aggrecan.

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Citations

Mar 20, 2003·Brain Research. Developmental Brain Research·Jean-François Colas, Gary C Schoenwolf
Feb 24, 2004·Molecular Biology of the Cell·Yaojiong WuBurton B Yang
Feb 20, 2013·The FEBS Journal·Megan S Lord, John M Whitelock
Jan 25, 2006·The Journal of Biological Chemistry·Peng-Sheng ZhengBurton B Yang
Nov 4, 2004·Journal of Cell Science·Peng-Sheng ZhengBurton B Yang

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