We review exciting
recent advances in protein degradation, with
a focus on chromatin structure. In our analysis of the literature,
we highlight studies of kinetic control of protein stability for cohesin,
condensin, ATP-dependent chromatin remodeling, and pioneer transcription
factors. With new connections emerging between chromatin remodeling
and genome structure, we anticipate exciting developments at the intersection
of these topics to be revealed in the coming years. Moreover, we pay
special attention to the 20-year anniversary of PROTACs, with an overview
of E3 ligase/target pairings and central questions that might lead
to the next generation of PROTACs with an expanded scope and generality.
While steady-state experimental measurements with constitutive genome
editing are impactful, we highlight complementary approaches for rapid
kinetic protein degradation to uncover early targeting functions and
to understand the central determinants of genome structure–function
relationships.
The liver is home to five known human hepatitis viruses (hepatitis A virus–hepatitis E virus). Despite being phylogenetically unrelated, these viruses replicate and spread in the liver without causing apparent cytopathic effects, and all have evolved strategies to counteract antibody-mediated inhibition of virus spread. In this review, we discuss the current understanding regarding the spread mechanisms for these viruses with an attempt to extract common principles and identify key questions for future studies.
Chemical warfare nerve agents (CWNAs) present a global threat to both military and civilian populations. The acute toxicity of CWNAs stems from their ability to effectively inhibit acetylcholinesterase (AChE). This inhibition can lead to uncontrolled cholinergic cellular signaling, resulting in cholinergic crisis and, ultimately, death. Although the current FDA-approved standard of care is moderately effective when administered early, development of novel treatment strategies is necessary. Butyrylcholinesterase (BChE) is an enzyme which displays a high degree of structural homology to AChE. Unlike AChE, the roles of BChE are uncertain and possibilities are still being explored. However, BChE appears to primarily serve as a bioscavenger of toxic esters due to its ability to accommodate a wide variety of substrates within its active site. Like AChE, BChE is also readily inhibited by CWNAs. Due to its high affinity for binding CWNAs, and that null-BChE yields no apparent health effects, exogenous BChE has been explored as a candidate therapeutic for CWNA intoxication. Despite years of research, minimal strides have been made to develop a catalytic bioscavenger. Furthermore, BChE is only in early clinical trials as a stoichiometric bioscavenger of CWNAs, and large quantities must be administered to treat CWNA toxicity. Here, we describe previously unidentified mutations to residues within and adjacent to the acyl binding pocket (positions 282–285 were mutagenized from YGTP to NHML) of BChE that confer catalytic degradation of the CWNA, sarin. These mutations, along with corresponding future efforts, may finally lead to a novel therapeutic to combat CWNA intoxication.
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