Structures of a bi-functional Kunitz-type STI family inhibitor of serine and aspartic proteases: could the aspartic protease inhibition have evolved from a canonical serine protease-binding loop?

Guerra, Yasel, Valiente, Pedro A., Pons, Tirso, Berry, Colin and Rudiño-Piñera, Enrique 2016. Structures of a bi-functional Kunitz-type STI family inhibitor of serine and aspartic proteases: could the aspartic protease inhibition have evolved from a canonical serine protease-binding loop? Journal of Structural Biology 195 (2) , pp. 259-271. 10.1016/j.jsb.2016.06.014

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Abstract

Bi-functional inhibitors from the Kunitz-type soybean trypsin inhibitor (STI) family are glycosylated proteins able to inhibit serine and aspartic proteases. Here we report six crystal structures of the wild-type and a non-glycosylated mutant of the bifunctional inhibitor E3Ad obtained at different pH values and space groups. The crystal structures show that E3Ad adopts the typical β-trefoil fold of the STI family exhibiting some conformational changes due to pH variations and crystal packing. Despite the high sequence identity with a recently reported potato cathepsin D inhibitor (PDI), three-dimensional structures obtained in this work show a significant conformational change in the protease-binding loop proposed for aspartic protease inhibition. The E3Ad binding loop for serine protease inhibition is also proposed, based on structural similarity with a novel non-canonical conformation described for the double-headed inhibitor API-A from the Kunitz-type STI family. In addition, structural and sequence analyses suggest that bifunctional inhibitors of serine and aspartic proteases from the Kunitz-type STI family are more similar to double-headed inhibitor API-A than other inhibitors with a canonical protease-binding loop.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Subjects:	Q Science > QH Natural history > QH301 Biology
Uncontrolled Keywords:	aspartic protease inhibitors, Kunitz-type STI family inhibitors, bi-functional inhibitors, plant protease inhibitors, β-trefoil fold
Publisher:	Elsevier
ISSN:	1047-8477
Date of First Compliant Deposit:	4 May 2017
Date of Acceptance:	18 June 2016
Last Modified:	11 Jul 2017 16:17
URI:	http://orca.cf.ac.uk/id/eprint/95774

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