The Lawrence Lab website (lawrence-lab.org) is live and we are hiring for our launch in Jan 2025!

We combine high resolution structure 🔬 and cell biology 🧪🧫 approaches to define mechanisms of stress response signaling in health and disease.

Live postings below--Please RT and send to recent grads!

We propose a model in which the ISR signaling dial is set by the ratio of A-State:I-State eIF2B conformations, which can be tuned by the presence of effectors or by mutating Switch-helix side-chain interactions. [8/10]

Endogenously edited cell lines containing rationally designed switch-helix mutations demonstrated that engineering switch-helix conformation can be used to program ISR signaling states in cells. [7/10]

Mutational analysis and in vitro biochemical assays probing enzymatic activity, conformation, and eIF2B assembly state confirmed that conformation of our “Switch-Helix” is sufficient to define the global conformation and activity of eIF2B. [6/10]

cryo-EM revealed that this helix lies at the fulcrum of the rotational motion and displays two distinct side-chain orientations, suggesting it may have a switch-like nature. [5/10]

Hydrogen-Deuterium Exchange-Mass Spectrometry (HDX-MS) revealed dramatic remodeling of a single alpha helix located at the core of the eIF2B complex in response to inhibition by eIF2-P, along with more subtle remodeling across other regions of the complex. [4/10]

eIF2B activity is controlled by conformation. Upon stress, the eIF2-P inhibitor prompts eIF2B subunits to rotate around a central axis, resembling the flapping of a butterfly’s wings. How is conformational change coordinated across 10 subunits? 3/10

Depending on context, ISR can promote homeostasis or drive age-related disease. These outcomes depend on the activity of eIF2B, a 500-kDa heterodecameric guanine GEF. Stress-responsive inhibition of eIF2B halts translation and prompts expression of stress-responsive genes.  2/10