Abstract
Tissue inhibitor of metalloproteinases (TIMPs) are endogenous inhibitor proteins of matrix metalloproteinases and contain 12 cysteine residues that are conserved among TIMPs, and which are important for their activity and structure. In the present study, three tryptophan residues conserved among TIMPs were revealed to be important for the secretion of TIMP-2. Replacement of conserved tryptophan residues in TIMP-2 with alanine led to a decrease in extracellular TIMP-2 levels and an increase in intracellular TIMP-2 levels. Furthermore, wild-type TIMP-2 and TIMP-2 mutated at unconserved tryptophan residues mainly localized in the Golgi apparatus, while TIMP-2 proteins mutated at conserved tryptophan were mainly observed in the endoplasmic reticulum (ER). This indicated that conserved tryptophan is essential for transporting TIMP-2 from the ER to Golgi apparatus. These observations suggested that conserved tryptophan residues among the TIMP family of proteins have critical roles for ER-Golgi transport and subsequent secretion of TIMP-2.
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