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Here, we shed physico-chemical light on major kinase signal transduction cascades in cell proliferation in the Ras network, MAPK and PI3K/AKT/mTOR. The cascades respond to external stimuli. The kinases are allosterically activated and relay the signal, leading to cell growth and division. The pathways are crosslinked, with the output of one pathway influencing the other. The effectiveness of their allosteric signaling relay stems from coordinated speed and precision. These qualities are essential for cell life-yet exactly how they are obtained and regulated has challenged the community over four decades. Here, we define their nature by their kinases' repertoires, substrate specificities and breadth, activation and autoinhibition mechanisms, catalytic rates, interactions, and their dilution state. The cascades are lodged in a dense molecular condensate phase at the membrane adjoining RTK clusters, where their assemblies promote specific, productive signaling. Aiming to shed further physico-chemical light, we ask (i) how starting the cascades with a single substrate and ending with hundreds is still labeled specific; (ii) what we can learn from their different number of mutations; and (iii) why B-Raf unique side-to-side inverse dimerization slows ERK activation and signaling. We point to the (iv) chemical mechanics of the distributions of rates of the crucial MAPK cascade: slower at the top and rapid at the bottom. Finally, the cascades provide inspiration for pharmacological perspectives. Collectively, our updated physico-chemical outlook provides the molecular basis of targeting protein kinases in cancer and spans mechanisms and scales, from conformational landscapes to membraneless organelles, cells and systems levels. Show less

For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, Show less

The XPD family of helicases, that includes human disease-related FANCJ, DDX11 and RTEL1, are Superfamily two helicases that contain an iron-sulphur cluster domain, translocate on ssDNA in a 5'-3' direction and play important roles in genome stability. Consequently, mutations in several of these family members in eukaryotes cause human diseases. Family members in bacteria, such as the DinG helicase from Escherichia coli, are also involved in DNA repair. Here we present crystal structures of complexes of DinG bound to single-stranded DNA (ssDNA) in the presence and absence of an ATP analogue (ADP•BeF₃), that suggest a mechanism for 5'-3' translocation along the ssDNA substrate. This proposed mechanism has implications for how those enzymes of the XPD family that recognise bulky DNA lesions might stall at these as the first step in initiating DNA repair. Biochemical data reveal roles for conserved residues that are mutated in human diseases. Show less