Structural analysis of clinically relevant pathogenic G6PD variants reveals the importance of tetramerization for G6PD activity

Matters
Anna D Cunningham, Daria Mochly-Rosen

Abstract

Over 220 different amino acid variants have been identified in human glucose-6-phosphate dehydrogenase (G6PD), covering over 30% of the protein sequence. Many of these variants are pathogenic, causing varying degrees of G6PD deficiency with symptoms ranging from severe chronic anemia (class I) to milder triggered hemolytic episodes (classes II and III). The phenotypic effects of most G6PD variants have been reported, providing an opportunity to correlate phenotypic and structural information. In particular, we sought to investigate the tetramer interface of G6PD in relation to pathogenic variation, as there are conflicting reports indicating the importance of tetramerization for G6PD activity. Using a three-dimensional spatial scan statistic, hotspots of structural enrichment were identified for each class of pathogenic G6PD variants. Class I variants, the most phenotypically severe, were enriched at the dimer interface, consistent with previous evidence that dimerization is essential for G6PD activity. Class II variants were enriched near the tetramer interface, suggesting that tetramerization is also important for G6PD activity. This analysis explains why these two classes, both yielding 10% or less G6PD activity as compared ...Continue Reading

References

Apr 29, 2005·Acta Crystallographica. Section D, Biological Crystallography·Masayo KotakaMargaret J Adams

❮ Previous
Next ❯

Citations

Jul 24, 2020·Blood·Lucio LuzzattoRosario Notaro
Jan 21, 2021·Proceedings of the National Academy of Sciences of the United States of America·Naoki HorikoshiSoichi Wakatsuki

❮ Previous
Next ❯

Software Mentioned

SIFT
PolyPhen2

Related Concepts

Related Feeds

Anemia

Anemia develops when your blood lacks enough healthy red blood cells. Anemia of inflammation (AI, also called anemia of chronic disease) is a common, typically normocytic, normochromic anemia that is caused by an underlying inflammatory disease. Here is the latest research on anemia.