Three-dimensional models of four mouse mast cell chymases: Identification of proteoglycan binding regions and protease-specific antigenic epitopes

Andrej Šali, Ryoji Matsumoto, H. Patrick McNeil, Martin Karplus*, Richard L. Stevens

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

105 Citations (Scopus)

Abstract

Mouse mast cell protease (mMCP) 1, mMCP-2, mMCP-4, and mMCP-5 are serine proteases which are predicted to have chymotryptic specificity (chymases). They are bound to negatively charged heparin or chondroitin sulfate proteoglycans and are stored in secretory granules. Three-dimensional (3D) models of these four proteases were constructed with a comparative molecular modeling technique based on satisfaction of spatial constraints. The models were used to predict immunogenic epitopes and surface regions that are likely to interact with proteoglycans. Nine potential antigenic segments in the four chymases were identified on the basis of solvent accessibility, protrusion, flexibility, and sequence variability. These segments are suitable epitopes for preparation of protease-specific antipeptide immunoglobulin. Two regions with net charges ranging from +6 to +10 at neutral pH were found on the surfaces of mMCP-4 and mMCP-5. The two regions are located far from the substrate binding cleft at diametrically opposite ends of the folded proteases. A strong positive electrostatic potential surrounds the two regions. Thus, they are good candidates for binding sites that interact with heparin proteoglycan in the granules of serosal mast cells. In contrast, mMCP-1 and mMCP-2, which are present in granules of mucosal mast cells that contain chondroitin sulfate, lack one of these regions and have a lower charge density in the other. The differences between the 3D models provide a structural basis for the selective localization of specific chymases within mouse mast cells that contain different proteoglycans.

Original languageEnglish
Pages (from-to)9023-9034
Number of pages12
JournalJournal of Biological Chemistry
Volume268
Issue number12
Publication statusPublished - 25 Apr 1993
Externally publishedYes

Fingerprint Dive into the research topics of 'Three-dimensional models of four mouse mast cell chymases: Identification of proteoglycan binding regions and protease-specific antigenic epitopes'. Together they form a unique fingerprint.

Cite this