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Darwin, K Heran
How does one help a struggling trainee, in or out of their own lab?
PMID: 37646308
ISSN: 1469-3178
CID: 5618322

Aldehyde accumulation in Mycobacterium tuberculosis with defective proteasomal degradation results in copper sensitivity

Limón, Gina; Samhadaneh, Nora M; Pironti, Alejandro; Darwin, K Heran
PMID: 37350636
ISSN: 2150-7511
CID: 5542942


Darwin, K Heran; Aldridge, Bree; Seeliger, Jessica; Shen, Aimee; Stanley, Sarah
Can we do better when it comes to the "other-race effect"?
PMID: 36876580
ISSN: 1469-3178
CID: 5432552

The β-Grasp Domain of Proteasomal ATPase Mpa Makes Critical Contacts with the Mycobacterium tuberculosis 20S Core Particle to Facilitate Degradation

Xiao, Xiansha; Feng, Xiang; Yoo, Jin Hee; Kovach, Amanda; Darwin, K Heran; Li, Huilin
Mycobacterium tuberculosis possesses a Pup-proteasome system analogous to the eukaryotic ubiquitin-proteasome pathway. We have previously shown that the hexameric mycobacterial proteasome ATPase (Mpa) recruits pupylated protein substrates via interactions between amino-terminal coiled-coils in Mpa monomers and the degradation tag Pup. However, it is unclear how Mpa rings interact with a proteasome due to the presence of a carboxyl-terminal β-grasp domain unique to Mpa homologues that makes the interaction highly unstable. Here, we describe newly identified critical interactions between Mpa and 20S core proteasomes. Interestingly, the Mpa C-terminal GQYL motif binds the 20S core particle activation pocket differently than the same motif of the ATP-independent proteasome accessory factor PafE. We further found that the β-hairpin of the Mpa β-grasp domain interacts variably with the H0 helix on top of the 20S core particle via a series of ionic and hydrogen-bond interactions. Individually mutating several involved residues reduced Mpa-mediated protein degradation both <i>in vitro</i> and <i>in vivo</i>. <b>IMPORTANCE</b> The Pup-proteasome system in Mycobacterium tuberculosis is critical for this species to cause lethal infections in mice. Investigating the molecular mechanism of how the Mpa ATPase recruits and unfolds pupylated substrates to the 20S proteasomal core particle for degradation will be essential to fully understand how degradation is regulated, and the structural information we report may be useful for the development of new tuberculosis chemotherapies.
PMID: 35993699
ISSN: 2379-5042
CID: 5365662

The mind of a scientist

Darwin, K Heran
There are many paths into and through academic science. Heran Darwin describes how she eventually got hooked on research.
PMID: 36102812
ISSN: 1469-3178
CID: 5332842

A conserved loop sequence of the proteasome system depupylase Dop regulates substrate selectivity in Mycobacterium tuberculosis

Yoo, Jin Hee; Kahne, Shoshanna C; Darwin, K Heran
Mycobacteria use a proteasome system that is similar to a eukaryotic proteasome but do not use ubiquitin to target proteins for degradation. Instead, mycobacteria encode a prokaryotic ubiquitin-like protein (Pup) that post-translationally modifies proteins to mark them for proteolysis. Pupylation occurs on lysines of targeted proteins and is catalyzed by the ligase PafA. Like ubiquitylation, pupylation can be reversed by the depupylase Dop, which shares high structural similarity with PafA. Unique to Dop near its active site is a disordered loop of approximately 40 amino acids that is highly conserved among diverse dop-containing bacterial genera. To understand the function of this domain, we deleted discrete sequences from the Dop loop and assessed pupylation of mutant strains in Mycobacterium tuberculosis. We determined that various Dop loop mutations resulted in altered pupylome profiles, in particular when mutant dop alleles were overexpressed. Taken together, our data suggest these conserved amino acids play a role in substrate selectivity for Dop.
PMID: 36100038
ISSN: 1083-351x
CID: 5336172

Waste management

Darwin, K Heran
Research in the life sciences is an inherently wasteful endeavor. Could we all do better to reduce waste by our laboratories?
PMID: 35507730
ISSN: 1469-3178
CID: 5216212

The aldehyde hypothesis: metabolic intermediates as antimicrobial effectors

Darwin, K Heran; Stanley, Sarah A
There are many reactive intermediates found in metabolic pathways. Could these potentially toxic molecules be exploited for an organism's benefit? We propose that during certain microbial infections, the production of inherently reactive aldehydes by an infected host is a previously unappreciated innate immune defence mechanism. While there has been a significant focus on the effects of aldehydes on mammalian physiology, the idea that they might be exploited or purposefully induced to kill pathogens is new. Given that aldehydes are made as parts of metabolic programmes that accompany immune cell activation by the cytokine interferon-gamma (IFN-γ) during infections, we hypothesize that aldehydes are among the arsenal of IFN-γ-inducible effectors needed for pathogen control.
PMID: 35414258
ISSN: 2046-2441
CID: 5201932


Darwin, K Heran
As COVID wanes and scientific conferences come back, some advice on how to deal with, organise and enjoy sharing science at meetings.
PMID: 35301788
ISSN: 1469-3178
CID: 5190552

Bench science

Darwin, K Heran
PIs do not need to stay away from bench work; in fact, they are often overall the best and most experienced experimentalists in the lab.
PMID: 34927345
ISSN: 1469-3178
CID: 5108702