Structure, function and phylogeny of zinc-α2-glycoprotein in health and disease

Zinc-α2-glycoprotein (ZAG) is a 42kDa non-classical major histocompatibility complex (MHC) class Iadipokine excreted around the body that regulates body mass through lipid metabolism. Abnormalexpression of ZAG occurs in diseases such as cachexia and obesity, with studies suggesting that ZAGhas a potential use as a biomarker in the identification of cancer. Recent literature has identified bindingsites within the groove of the α1α2 domain and, unexpectedly, in the α3 domain when bound in atetramer. To identify these sites and investigate the α3 domain's ability to form a β-barrel, recombinantZAG was expressed from a pET-23a(+) plasmid in a BL21 DE3 Star pRARE E.coli host. Whilst thisinvestigation was interrupted due to COVID-19, other characteristics of ZAG were investigated.Phylogenetic analysis revealed that ZAG was more closely related to non-classical MHC class I relatedproteins MICA, MICB, HLA-A, -E, -F, -G and MR1, and evolved linearly with placental mammals,where marsupial mammalian ZAG is more diverged. An interactive ZAG database allowing for theobservational analysis of variant mutations in ZAG from cancer patients was developed, revealing thatmutations in the RGD triad and lipid binding residues may cause metabolic changes that are requiredfor the progression of cancer.