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The major human and mouse granzymes are structurally and functionally divergent

Approximately 2% of mammalian genes encode proteases. Comparative genomics reveals that those involved in immunity and reproduction show the most interspecies diversity and evidence of positive selection during evolution. This is particularly true of granzymes, the cytotoxic proteases of natural kil...

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Autores principales: Kaiserman, Dion, Bird, Catherina H., Sun, Jiuru, Matthews, Antony, Ung, Kheng, Whisstock, James C., Thompson, Philip E., Trapani, Joseph A., Bird, Phillip I.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2064598/
https://www.ncbi.nlm.nih.gov/pubmed/17116752
http://dx.doi.org/10.1083/jcb.200606073
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author Kaiserman, Dion
Bird, Catherina H.
Sun, Jiuru
Matthews, Antony
Ung, Kheng
Whisstock, James C.
Thompson, Philip E.
Trapani, Joseph A.
Bird, Phillip I.
author_facet Kaiserman, Dion
Bird, Catherina H.
Sun, Jiuru
Matthews, Antony
Ung, Kheng
Whisstock, James C.
Thompson, Philip E.
Trapani, Joseph A.
Bird, Phillip I.
author_sort Kaiserman, Dion
collection PubMed
description Approximately 2% of mammalian genes encode proteases. Comparative genomics reveals that those involved in immunity and reproduction show the most interspecies diversity and evidence of positive selection during evolution. This is particularly true of granzymes, the cytotoxic proteases of natural killer cells and CD8(+) T cells. There are 5 granzyme genes in humans and 10 in mice, and it is suggested that granzymes evolve to meet species-specific immune challenge through gene duplication and more subtle alterations to substrate specificity. We show that mouse and human granzyme B have distinct structural and functional characteristics. Specifically, mouse granzyme B is 30 times less cytotoxic than human granzyme B and does not require Bid for killing but regains cytotoxicity on engineering of its active site cleft. We also show that mouse granzyme A is considerably more cytotoxic than human granzyme A. These results demonstrate that even “orthologous” granzymes have species-specific functions, having evolved in distinct environments that pose different challenges.
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spelling pubmed-20645982007-11-29 The major human and mouse granzymes are structurally and functionally divergent Kaiserman, Dion Bird, Catherina H. Sun, Jiuru Matthews, Antony Ung, Kheng Whisstock, James C. Thompson, Philip E. Trapani, Joseph A. Bird, Phillip I. J Cell Biol Research Articles Approximately 2% of mammalian genes encode proteases. Comparative genomics reveals that those involved in immunity and reproduction show the most interspecies diversity and evidence of positive selection during evolution. This is particularly true of granzymes, the cytotoxic proteases of natural killer cells and CD8(+) T cells. There are 5 granzyme genes in humans and 10 in mice, and it is suggested that granzymes evolve to meet species-specific immune challenge through gene duplication and more subtle alterations to substrate specificity. We show that mouse and human granzyme B have distinct structural and functional characteristics. Specifically, mouse granzyme B is 30 times less cytotoxic than human granzyme B and does not require Bid for killing but regains cytotoxicity on engineering of its active site cleft. We also show that mouse granzyme A is considerably more cytotoxic than human granzyme A. These results demonstrate that even “orthologous” granzymes have species-specific functions, having evolved in distinct environments that pose different challenges. The Rockefeller University Press 2006-11-20 /pmc/articles/PMC2064598/ /pubmed/17116752 http://dx.doi.org/10.1083/jcb.200606073 Text en Copyright © 2006, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Kaiserman, Dion
Bird, Catherina H.
Sun, Jiuru
Matthews, Antony
Ung, Kheng
Whisstock, James C.
Thompson, Philip E.
Trapani, Joseph A.
Bird, Phillip I.
The major human and mouse granzymes are structurally and functionally divergent
title The major human and mouse granzymes are structurally and functionally divergent
title_full The major human and mouse granzymes are structurally and functionally divergent
title_fullStr The major human and mouse granzymes are structurally and functionally divergent
title_full_unstemmed The major human and mouse granzymes are structurally and functionally divergent
title_short The major human and mouse granzymes are structurally and functionally divergent
title_sort major human and mouse granzymes are structurally and functionally divergent
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2064598/
https://www.ncbi.nlm.nih.gov/pubmed/17116752
http://dx.doi.org/10.1083/jcb.200606073
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