An inflammatory role for the mammalian carboxypeptidase inhibitor latexin: relationship to cystatins and the tumor suppressor TIG1.
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 A 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.
Aagaard
Anna
A
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.
Listwan
Pawel
P
Cowieson
Nathan
N
Huber
Thomas
T
Ravasi
Timothy
T
Wells
Christine A
CA
Flanagan
Jack U
JU
Kellie
Stuart
S
Hume
David A
DA
Kobe
Bostjan
B
Martin
Jennifer L
JL
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000737:chemistry* / Q000502:physiology; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D015891:Cystatins / Q000737:chemistry*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry*; D017510:Protein Folding; D051381:Rats; D025521:Tumor Suppressor Proteins / Q000737:chemistry*
D000941:Antigens; D015891:Cystatins; C086812:Lxn protein, rat; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011480:Protease Inhibitors; C452562:RARRES1 protein, human; D025521:Tumor Suppressor Proteins; C000618833:latexin protein, mouse; D002268:Carboxypeptidases