Our findings establish a critical link between HemAC

Our findings establish a critical link between HemAC-Lm dimeric structure and cAMP synthesis that helps in explaining how globin-A domain influences AC domain. The following possible homodimeric structure of wild type full length HemAC-Lm has been proposed to explain the role of this globin-A domain in cAMP synthesis. (i) It can form dimeric structure by parallel interaction between two monomers (Fig. 6A) but the primary structure analysis indicates that the globin-A domain is far apart from AC domain. (ii) Only globin-A &-B domains of each monomer may interact in dimeric structure (Fig. 6B). In this structure, the globin-B domain will interact with AC domain and subsequently the enzyme will be inactive. (iii) Another possible dimeric structure is formed by domain swapping only between globin-A and -B domains of each monomer (Fig. 6C). This structure will be ruled out due to the binding of globin-B domain with AC domain. (iv) We now propose that the interaction between globin-A and globin-B domains enables the enzyme to be engaged in a type of “domain swapping” shown in Fig. 6D, which in turn allows O2 dependent conformational change in the globin-A domain that sequentially stimulates the catalytic activity of the adenylate cyclase domain located on adjacent subunits. This arrangement possibly circumvents a physical barrier for interaction between globin-B domain and catalytic domain located on the same subunit. It is still unknown which amino Cyclosporine sale residues are responsible for the interaction between globin-A and AC (catalytic) domains. Domain swapping as envisioned for HemAC-Lm is a comparatively common characteristic among heme proteins, like cytochrome c [28], [29], [30], [31], myoglobin [32], [33], NO synthase [34], nitrite reductase [35], hemophore HasA [36] and methyl accepting chemotaxis protein [37]. However, the swapped Mb dimeric structure displays a similar oxygen-binding properties as that of its monomer [32]. Recently, researchers have suggested that the domain-swapped structure of dimeric cyt c displays different characteristics from those of its monomer [29], [31]. In general, domains from adjacent subunits interact with each other when oligomerization takes place in the evolution of the protein’s structure. Over time, the interaction of intrasubunit between domains linked together on the polypeptide chain is often replaced by intersubunit interactions, as the intrasubunit interaction does not create any selective pressure to be preserved after oligomerization [38]. It leads to conclude that, the polypeptide chain of HemAC-Lm probably acquired its bi-domain structure first, followed by its dimeric structure, which ultimately drives us to ensure the acceptability of intersubunit interactions between adjacent AC and globin-A domains for regulation.
Acknowledgments We thank Dr. Antoine Danchin (AMAbiotic SAS) for providing the strain TP610. This work was supported by Council of Scientific and Industrial Research (CSIR) Project BSC 0114, CSIR-Shyama Prasad Mukherjee fellowships (to S.S.S.), CSIR fellowships (to J.R. and A.M), University Grants Commission fellowships (to A.A.).
Within the past 4 years, 4 whole-exome sequencing efforts, , , independently identified mutations in the gene as the cause of a wide spectrum of childhood-onset movement disorders. Affected children present with variable features, including persistent or paroxysmal choreic, myoclonic, myokymic, and/or dystonic movements involving the limbs, neck, and/or face. encodes adenylate cyclase 5, a membrane protein that converts adenosine triphosphate to 3′,5′-cyclic adenosine monophosphate and pyrophosphate. Interestingly, of 14 different mutations reported,, , , , , , 3 (c.1252C>T, p.Arg418Trp; c.1253G>A, p.Arg418Gln; and c.2176G>A, p.Ala726Thr) are recurrent, given that they have been identified in at least 2 unrelated families. Of these, p.Arg418Trp has been found in the majority of patients and presents with the most severe phenotype, indicating that there may be evidence of a genotype-phenotype correlation in -mutation-associated disease.