What if protein function could be triggered only when the right cell cues are present? With SMART, we combine split inteins and logic gating to create a programmable system for cell-specific protein ligation, thus opening new doors for synthetic biology and cell targeting.

Today, we introduce a nomenclature that can express discrete PTMs, proteoforms, nucleoforms, or situations where defined PTMs exist in an uncertain context and can describe how proteoforms are configured in functionally distinct complexes across biology. https://t.co/WrMYTXamIe

Congratulations to our Tom Muir @MuirLab on being awarded the @AmerChemSociety's Ralph F. Hirschmann Award in Peptide Chemistry for exceptional achievement in the field. Well done, Tom! Enjoy our story here: https://t.co/T26DeWQlFu

Congrats again to all our graduates!

And last but not least, we have Dr Yingzi Huang, who presented a wonderful seminar on her chromatin within the context of DNA damage. Stay tuned for this story…

Next, we have our newly minted Dr Esmat Hegazi, who gave an excellent talk on oncohistones. Look out for her work coming out soon… @esmathegazi

With the start of the new academic year comes several farewells from our lab, as senior members of the lab graduate. First off, congratulations to our “transposein” Dr Yi Hua, who is heading off to @Stanford for a postdoc with @aliceyting

Congratulations @MuirLab postdoc Jason Johansen-Leete on his Life Sciences Research Foundation Fellowship, sponsored by Amgen, for his project: “High-resolution mapping of the BAF interactome with novel chemoproteomic technologies.” Well done, Jason!

Congratulations to Tom for receiving the Ralph Hirschmann award in Peptide Chemistry! @PrincetonChem https://t.co/HS2syixNKo

Nature research paper: Programmable protein ligation on cell surfaces https://t.co/sYlmpJYQpA

The @MuirLab introduces a groundbreaking protein activation platform that allows “exquisite precision,” in @Nature last week. Enjoy our story on this @NIH funded research by Christian, Girum, Nicholas, Xuanjia, Yutong and Tom: https://t.co/paiDEOoOlS

Very happy to share this preview in @TrendsinBiotech two cool intein papers just out in @ScienceMagazine by @GMBurslem, @ophirshalem & @MuirLab. Beautifully written by my new postdoc, Kevin Schiefelbien🤩 @Penn @PrincetonChem https://t.co/2K2TszOc9C

Congratulations to Christian, Girum, Nick, Xuanjia, and Yutong! Link: https://t.co/KoOKDGH6Pd @PrincetonChem @PrincetonInnov

We anticipate that this technology will enable targeted formation of biomolecules with reduced off-target toxicity. This paper is the start of many applications for SMART and stay tuned for more!

While our prior applications of SMART involve a splice-and-retain mechanism, we also show that we can engineer SMART to perform a novel AND-gated splice-and-release operation. This is applied to the reconstitution of an active interleukin 1B from inactive fragments.

We are also able to show that SMART works with a range of targeting vectors, ranging from scFvs to peptides to small molecules. We also show that we can perform AND-gated enzymatic proximity labeling using APEX2 and photocatalytic proximity labeling using micro-Map

However, given the widespread applications of AND-gated logic, we chose to focus on efforts on this front, and showed that we can do targeted cell depletion with exquisite selectivity for cells displaying the right combination of epitopes

We are also able to develop other logic gated operations using this system. By engineering split-intein cages and SpyCatcher, we show that our system is able to operate a 3-input AND/NOT gate.

This project started with the development of a split-SpyCatcher that is faithfully reconstituted when two distinct epitopes on cell surfaces is targeted.

SMART relies on the fundamental AND-gated nature of split-inteins. When caged appropriately, we can use epitopes on the cell surface to drive the ligation of two inactive protein fragments to reconstitute a functional protein.