QSOX – a structural puzzle solved

Published on Author Colin Thorpe

Depending on the source, QSOX sequences start with one or two thioredoxin domains (the bar diagram is for metazoans).  The remaining two domains are common to all QSOXs: a helix-rich region (HRR) and a flavin-binding domain (Erv/ALR, yellow).  The latter is the engine of QSOX catalysis – driving the generation of disulfide bonds and reducing oxygen to hydrogen peroxide.  In addition to QSOX, this Erv/ALR domain is found in a number of small dimeric stand-alone sulfhydryl oxidases – exemplified by the structure of yeast Erv2p [PubMed].

The origins of QSOX lie deep in the eukaryotic tree – before the divergence of the fungi.  So where did that mysterious HRR domain come from?  Our sequence analyses were uninformative.

In a recent paper, the Fass laboratory (Alon et al.) show that the HRR domain from human QSOX1 bears a remarkable structural resemblance to the flavin binding domain of Erv/ALR itself.  Even the relative alignment of helices between the HRR and Erv/ALR domains have been preserved from the dimeric Erv2p protein.

Gene duplication of the 4-helix-flavin-binding-bundle (a signature of these sulfhydryl oxidase structures) was seemingly followed by a loss of FAD binding determinants and the emergence of the flavin-free HRR domain.  The combination of thioredoxin, and active and degenerate Erv/ALR domains led to the proficient QSOX catalysts that we study today.

Now, where did the Erv/ALR flavin-binding domain (shown in purple above) come from?

Print Friendly, PDF & Email