The Muir lab investigates the physiochemical basis of protein function in complex systems of biomedical interest.
Princeton, NJ
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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…
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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
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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
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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.
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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
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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
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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.
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This project started with the development of a split-SpyCatcher that is faithfully reconstituted when two distinct epitopes on cell surfaces is targeted.
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Congratulations to our second years Alan and Chuqi for passing their general exams and officially becoming PhD candidates!
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That’s a wrap for our 3rd year seminars, who all did a fantastic job presenting updates on their research progress!
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In particular, we use CAGE to study the dynamics of phosphorylation events, which enable us to identify and target kinases involved in these oncofusion disease pathways!
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Our CAGE system allows us to post-translationally turn on the activity of oncogenic proteins from inactive fragments and to study their downstream signaling events with temporal control.
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We’ll spare you all the details of the manuscript so you can discover it on your own, but a key application of this work was being able to install a phosphotyrosine PTM into the folded ACF chromatin remodeling complex, at a position near a key regulatory region inaccessible to existing semisynthetic methods. In vitro remodeling assays which show that this phosphotyrosine decreases ACF activity and we think this may be the first PTM on a remodeler shown to directly affect remodeling activity.
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To showcase the efficacy of protein transposition, we were able to insert peptide sequences into a GFP loop, and an abiotic PEG polymer into the backbone of dCas9 with ease. The transposition process did not impact the function of the proteins. To push our system even further, we used our transposition system on a folded protein complex, namely ACF remodeler complex consisting of ACF1 and SMARCA5! We performed protein transposition on SMARCA5 and were able to install 1) protein tags for pulldown assays, 2) functional peptide sequence to turn on protein activity 3) photocrosslinkers for interactomic assays and 4) PTMs to probe biochemical function. This transposition also work in nucleo, which enables us to install functional peptide regions within the context of isolated nuclei.
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We historically have been able to modify the N- and C- termini of proteins using our ultra-fast split inteins, but being able to swap out internal regions of folded proteins has been a significant challenge in the field. We took inspiration from nature, where DNA transposases use sequence-specific DNA regions to cut-and-paste genetic material from genomic location to another. To solve this problem on the protein side, we used an optimal atypical/typical split intein pair to swap in a peptide/abiotic transposon, enabling the insertion of this new material into a folded protein. Efficient protein transposition was observed when we chose a split intein pair with synchronized splicing kinetics and minimal perturbation to the folded protein structure and function.
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Congratulations to our second years @KayleeCappuccio and @MerzZoe70551 for winning teaching awards for their excellent work as teaching assistants this year!
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Congratulations to our two newly minted PhDs Drs Hengyuan Liu and Steven Bodine! We’re going to miss you!
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Congratulations to our newest inductee into the @theNASciences! @PrincetonChem
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Additionally, congratulations to our second year Zoe Merz for attaining an Honorable Mention in this year’s @NSF GRFP
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Congratulations to our postdoc @jeremyaowen on becoming a @DamonRunyon Quantitative Biology fellow!
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Thanks @realJimWells for an inspiring talk on protein engineering and tools for studying protein surfaceome biology! Our students especially enjoyed the research and career discussions that were had throughout the day.
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We are also bidding adieu to deLIGHTful senior postdoc and protein semi synthesis guru Nir Hananya @HananyaNir, who will be starting his own lab at @TechnionLive 3/4
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We say goodbye to our protein whiz and intein master Christian Kofoed, who recently returned to Denmark 2/4
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Had a great time at the Muir Lab Holiday party! It was a great year with many new additions to the lab. Cannot wait to spend 2023 with y'all!!
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We're so sorry to see @MMMitchener go! She has been such a valuable Labmate and friend. Best of luck in Singapore!
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Updated lab photo with new members: @benjbuch, @junerzz, @jeremyaowen, Zoe Merz, Kaylee Cappuccio, Zhe Jiang, and Grium Erkalo! Please check out the webpage, muir.princeton.edu/!!
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Congrats to our amazing grad student @esmathegazi on her selection for the NIH CTSA TL1 Predoctoral Fellowship with NJACTS! njacts.rbhs.rutgers.edu/educ…
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Check out the latest review from the Muir lab on various methods for making asymmetric nucleosomes and their biological significance. This is taking the concept of a “histone code” to the next level! @MMMitchener @PrincetonChem pubs.acs.org/doi/10.1021/acs…
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