Identification of metal binding motifs in protein frameworks to develop novel remediation strategies for Hg2+ and Cr(VI).

Amino acid sequences in metal-binding proteins with chelating properties offer exciting applications in biotechnology and medical research. To enhance their application in bioremediation studies, we explicitly aimed to identify specific metal-binding chelating motifs in protein structures for two significant pollutants, such as mercury (Hg2+) and chromium Cr(V1). For this purpose, we have performed an extensive coordination chemistry approach by retrieving Hg2+ and Cr(V1) binding protein structures from the protein database and validated using the B-factor, a term defining uncertainty of the atoms and with occupancy to obtain the best binding motifs. Our analysis revealed that acidic amino acids like aspartic acid, glutamic acid, and basic amino acids such as cysteine and histidine are predominant in coordinating with these metals. The order of preference in Hg2+-bound structures is predicted to be Cys > His > Asp > Glu, and for Cr(V1) is His > Asp > Glu. Examination of the atomic coordinates and their distance from each metal revealed that the sulfur atoms of cysteine showing more preference towards Hg2+coordination with an atomic distance ranging from 1.5 to 2.9 Å. Likewise, oxygen atoms of aspartic acid, glutamic acid and nitrogen atoms of histidine are within 2 Å of Cr(V1) coordination. Based on these observations, we obtained C-C-C, C-X(2)-C-C-(X)2-C, H-C-H motifs for Hg2+, and D-X(1)-D, H-X(3)-E motif for Cr(V1) to be shared within the coordination space of 3 Å. As a future scope, we propose that the identified metal-binding chelating motifs are oligopeptides and can display on the surface of microorganisms such as Escherichia coli and Saccharomyces cerevisiae for effective removal of natural Hg2+ and Cr(V1) through biosorption. Hence, our results will provide the basis for futuristic bioremediation.

Exploring the structural significance of molecular switch mechanism alias motif phosphorylation in Wnt/ß-catenin and their crucial role in triple-negative breast cancer.

ß-Catenin, a key transcriptional factor involved in the canonical Wnt signaling pathway, is regulated by a cascade of phosphorylations and plays a major role in the progression of triple-negative breast cancer (TNBC). However, the phosphorylation induced conformational changes in a ß-Catenin is still poorly understood. Hence, we adopted a conventional molecular dynamics approach to study phosphorylations present in a sequence motif Ser 552 675 and Tyr670 of the ß-Catenin domain and analyzed in terms of structural transitions, bond formation, and folding-misfolding conformations. Our results unveil the ß-Catenin linear motif 549-555 (RRTSMGG) of armadillo repeats domain prefers order to disorder state. In contrast, helix C associated with 670-678 (YKKRLSVEL) motif prefers disorder to order upon phosphorylation of Ser 552 675 and Tyr670. In addition, the crucial secondary structural transition from α-helix to coil induced by phospho Ser552 and phospho Tyr670 of ß-Catenin ARM domain connecting helix C modifies conformational diversity and binding affinities of the complex interaction in functional regulation significantly. Moreover, the post phosphorylation disrupted the hydrogen bond interactions (Ser552-Arg549, Arg550-Asp546 and Ser675-Lys672) and abolished the residual alliance with hydrophobic interactions (Tyr670-Leu674) that easily interrupt in secondary structure packing as well as folding conformations connecting ARM and helix C (R10, 12 & R1C) compared to unphosphorylation. Our integrated computational analysis may help in shedding light on understanding the induced folding and unfolding pattern due to motif phosphorylations. Overall, our results provide an atomistic structural description of the way phosphorylation facilitates conformational and dynamic changes in ß-Catenin, a fundamental molecular switch mechanism in triple-negative breast cancer pathogenesis.