An inflammatory role for the mammalian carboxypeptidase inhibitor latexin: Relationship to cystatins and the tumor suppressor TIG1

Anna Aagaard, Pawel Listwan, Nathan Cowieson, Thomas Huber, Timothy Ravasi, Christine A. Wells, Jack U. Flanagan, Stuart Kellie, David A. Hume, Bostjan Kobe, Jennifer L. Martin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Latexin, the only known mammalian carboxypeptidase inhibitor, has no detectable sequence similarity with plant and parasite inhibitors, but it is related to a human putative tumor suppressor protein, TIG1. Latexin is expressed in the developing brain, and we find that it plays a role in inflammation, as it is expressed at high levels and is inducible in macrophages in concert with other protease inhibitors and potential protease targets. The crystal structure of mouse latexin, solved at 1.83 Å resolution, shows no structural relationship with other carboxypeptidase inhibitors. Furthermore, despite a lack of detectable sequence duplication, the structure incorporates two topologically analogous domains related by pseudo two-fold symmetry. Surprisingly, these domains share a cystatin fold architecture found in proteins that inhibit cysteine proteases, suggesting an evolutionary and possibly functional relationship. The structure of the tumor suppressor protein TIG1 was modeled, revealing its putative membrane binding surface.

Original languageEnglish (US)
Pages (from-to)309-317
Number of pages9
JournalStructure
Volume13
Issue number2
DOIs
StatePublished - Feb 2005

Bibliographical note

Funding Information:
We thank staff at BL8.2.2 for help in data collection, Catherine Latham for help with data collection and processing, and Alun Jones for mass spectrometry. Crystallographic data were measured at the Advanced Light Source, which is supported by the Director, Office of Science, Office of Basic Energy Sciences, Materials Sciences Division, of the U.S. Department of Energy under Contract No. DE-AC03-76SF00098 at the Lawrence Berkeley National Laboratory. This work was supported by a Postdoctoral Fellowship from the Swedish Foundation for International Cooperation in Research and Higher Education (STINT) to A.A., a National Health and Medical Research Council of Australia Senior Research Fellowship to B.K., an Australian Research Council (ARC) Senior Research Fellowship to J.L.M., and by the Cooperative Research Centre for Chronic Inflammatory Disease, and an ARC grant to J.L.M. and B.K.

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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