bims-tunefa 2020-09-13 papers

ACS Chem Biol. 2020 Sep 09.

Potent inhibition of Necroptosis by simultaneously targeting multiple effectors of the pathway.

Necroptosis is an inflammatory form of programmed cell death that has been implicated in various human diseases. Compound 2 is a more potent analogue of the published Compound 1 and inhibits necroptosis in human and murine cells at nanomolar concentrations. Several target engagement strategies were employed, including Cellular Thermal Shift Assays (CETSA) and diazirine-mediated photoaffinity labeling via a bifunctional photoaffinity probe derived from Compound 2. These target engagement studies demonstrate that Compound 2 binds to all three necroptotic effector proteins - mixed lineage kinase domain-like protein (MLKL), receptor-interacting serine/threonine protein kinase 1 (RIPK1) and receptor-interacting serine/threonine protein kinase 3 (RIPK3) - at different levels in vitro and in cells. Compound 2 also shows efficacy in vivo in a murine model of systemic inflammatory response syndrome (SIRS).

DOI: https://doi.org/10.1021/acschembio.0c00482

Trends Biochem Sci. 2020 Sep 08. pii: S0968-0004(20)30202-4. [Epub ahead of print]

Protein N-Terminal Acetylation: Structural Basis, Mechanism, Versatility, and Regulation.

Sunbin Deng, Ronen Marmorstein.

N-terminal acetylation (NTA) is one of the most widespread protein modifications, which occurs on most eukaryotic proteins, but is significantly less common on bacterial and archaea proteins. This modification is carried out by a family of enzymes called N-terminal acetyltransferases (NATs). To date, 12 NATs have been identified, harboring different composition, substrate specificity, and in some cases, modes of regulation. Recent structural and biochemical analysis of NAT proteins allows for a comparison of their molecular mechanisms and modes of regulation, which are described here. Although sharing an evolutionarily conserved fold and related catalytic mechanism, each catalytic subunit uses unique elements to mediate substrate-specific activity, and use NAT-type specific auxiliary and regulatory subunits, for their cellular functions.

Keywords: HYPK; IP(6); N-terminal acetylation; NATs; co-translational modification; enzyme mechanism; post-translational modification; ribosome

DOI: https://doi.org/10.1016/j.tibs.2020.08.005

Sci Signal. 2020 Sep 08. pii: eaay8690. [Epub ahead of print]13(648):

The hallmarks of cancer are also the hallmarks of wound healing.

Lucy MacCarthy-Morrogh, Paul Martin.

The Hanahan and Weinberg "hallmarks of cancer" papers provide a useful structure for considering the various mechanisms driving cancer progression, and the same might be useful for wound healing. In this Review, we highlight how tissue repair and cancer share cellular and molecular processes that are regulated in a wound but misregulated in cancer. From sustained proliferative signaling and the activation of invasion and angiogenesis to the promoting role of inflammation, there are many obvious parallels through which one process can inform the other. For some hallmarks, the parallels are more obscure. We propose some new prospective hallmarks that might apply to both cancer and wound healing and discuss how wounding, as in biopsy and surgery, might positively or negatively influence cancer in the clinic.

DOI: https://doi.org/10.1126/scisignal.aay8690