Alternate mRNA splicing in multiple human tryptase genes is predicted to regulate tetramer formation

Nicole E. Jackson, Hong Wei Wang, Katherine J. Bryant, H. Patrick McNeil, Ahsan Husain, Ke Liu, Nicodemus Tedla, Paul S. Thomas, Garry C. King, Anusha Hettiaratchi, Jennifer Cairns, John E. Hunt

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Tryptases are serine proteases that are thought to be uniquely and proteolytically active as tetramers. Crystallographic studies reveal that the active tetramer is a flat ring structure composed of four monomers, with their active sites arranged around a narrow central pore. This model explains why many of the preferred substrates of tryptase are short peptides; however, it does not explain how tryptase cleaves large protein substrates such as fibronectin, although a number of studies have reported in vitro mechanisms for generating active monomers that could digest larger substrates. Here we suggest that alternate mRNA splicing of human tryptase genes generates active tryptase monomers (or dimers). We have identified a conserved pattern of alternate splicing in four tryptase alleles (αII, βI, βIII, and δI), representing three distinct tryptase gene loci. When compared with their full-length counterparts, the splice variants use an alternate acceptor site within exon 4. This results in the deletion of 27 nucleotides within the central coding sequence and 9 amino acids from the translated protein product. Although modeling suggests that the deletion can be easily accommodated by the enzymes structurally, it is predicted to alter the specificity by enlarging the S1′ or S2′ binding pocket and results in the complete loss of the "47 loop," reported to be critical for the formation of tetramers. Although active monomers can be generated in vitro using a range of artificial conditions, we suggest that alternate splicing is the in vivo mechanism used to generate active tryptase that can cleave large protein substrates.

Original languageEnglish
Pages (from-to)34178-34187
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number49
DOIs
Publication statusPublished - 5 Dec 2008
Externally publishedYes

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