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Rapid expansion of the protein disulfide isomerase gene family facilitates the folding of venom peptides

Helena Safavi-Hemami,Qing Li,R. L. Jackson,A. Song,Wouter Boomsma,P. Bandyopadhyay,Christian W. Gruber,A. Purcell,M. Yandell,B. Olivera,L. Ellgaard

Published 2016 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance The majority of secreted proteins contain disulfide bonds that provide structural stability in the extracellular environment. The formation of correct disulfide bonds is assisted by the enzyme protein disulfide isomerase (PDI). Most secreted structural domains are ancient and widely distributed in all metazoans; in contrast, diverse sets of unique disulfide-rich structural domains have more recently evolved in venomous marine snails (superfamily Conoidea comprising >10,000 species). We have discovered a previously undescribed gene family encoding PDIs of unprecedented diversity. We suggest that these enzymes constitute an important part of the supporting molecular infrastructure required for properly folding the plethora of structural domains expressed in the venoms of snails in different conoidean lineages. Formation of correct disulfide bonds in the endoplasmic reticulum is a crucial step for folding proteins destined for secretion. Protein disulfide isomerases (PDIs) play a central role in this process. We report a previously unidentified, hypervariable family of PDIs that represents the most diverse gene family of oxidoreductases described in a single genus to date. These enzymes are highly expressed specifically in the venom glands of predatory cone snails, animals that synthesize a remarkably diverse set of cysteine-rich peptide toxins (conotoxins). Enzymes in this PDI family, termed conotoxin-specific PDIs, significantly and differentially accelerate the kinetics of disulfide-bond formation of several conotoxins. Our results are consistent with a unique biological scenario associated with protein folding: The diversification of a family of foldases can be correlated with the rapid evolution of an unprecedented diversity of disulfide-rich structural domains expressed by venomous marine snails in the superfamily Conoidea.

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