期刊
FEBS JOURNAL
卷 282, 期 2, 页码 341-360出版社
WILEY-BLACKWELL
DOI: 10.1111/febs.13138
关键词
disintegrin bitistatin; integrin antagonist; molecular evolution; NMR structure; snake venom protein
资金
- Ministerio de Economia y Competitividad, Madrid [BFU2010-17373]
- Generalitat Valenciana [PROMETEO/2010/005]
- CYTED [BIOTOX P211RT 0412]
Extant disintegrins, as found in the venoms of Viperidae and Crotalidae snakes (vipers and rattlesnakes, represent a family of polypeptides that block the function of beta 1 and beta 3 integrin receptors, both potently and with a high degree of selectivity. This toxin family owes its origin to the neo-functionalization of the extracellular region of an ADAM (a disintegrin and metalloprotease) molecule recruited into the snake venom gland proteome in the Jurassic. The evolutionary structural diversification of the disintegrin scaffold, from the ancestral long disintegrins to the more recently evolved medium-sized, dimeric and short disintegrins, involved the stepwise loss of pairs of class-specific disulfide linkages and the processing of the N-terminal region. NMR and crystal structures of medium-sized, dimeric and short disintegrins have been solved. However, the structure of a long disintegrin remained unknown. The present study reports the NMR solution structures of two disulfide bond conformers of the long disintegrin bitistatin from the African puff adder Bitis arietans. The findings provide insight into how a structural domain of the extracellular region of an ADAM molecule, recruited into and selectively expressed in the snake venom gland proteome as a PIII metalloprotease in the Jurassic, has subsequently been tranformed into a family of integrin receptor antagonists.
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