This paper was a tour de force and would not be possible without he help of so many collaborators like @juanbonifacino.bsky.social and many more. Thank you!!!

Strikingly, the presence of this frameshifted proteoform was necessary for myocardial contraction, as we showed in PLEKHM2-KO cells that required both the WT and frameshifted proteoforms to recover fully, leading to our model

Furthermore, we were able to show that this frameshifted version of PLEKHM2 generated a hyper-active version of this protein, which did not require activation of its canonical activator

Not only did the frameshift exist, it was highly conserved and encoded for an additional alpha-helix domain

Today our journey ends! We were able to find a highly conserved cellular +1 PRF signal in the gene PLEKHM2/SKIP

A few years ago, we published in Nature (nature.com/articles/s41...) detailing this artefact and noting that no true PRF signal existed in humans gave access to two overlapping open reading frames that both encoded something useful like in viruses

However the authors (nature.com/articles/nat...) and others in the field had unfortunately been using a reporter with a malicious splicing artefact, accidentally presenting PRF activity.

PRF is employed widely across viral clades from HIV-1, Sars-COV-2, RSV, Influenza, etc. However, there was always a chase to find the first real case of PRF occurring in a human, cellular gene. And in 2014, researchers believed that had found the first case in CCR5

Programmed Ribosomal Frameshifting (PRF) is a phenomena that has been studied extensively in viruses since the 80s. In short, a single RNA has the ability to code for multiple proteins by 'recoding' the genetic code i.e. having the ribosome change its reading frame mid-elongation

Excited to collaborate and have people join us! Please checkout the lab website above if you are interested!

Don’t leave us hanging Hiten!

Thus, any kind of SNARE can be processed universally by this single molecule machine. Check out the paper for more in-depth structural work! (5/5)

Combining in-vivo mass-spec, single molecule FRET, and time resolved cryoEM, we were able to determine that this NSF/Sec18 ring actually splits itself open from the side to accomodate SNAREs, thus completely bypassing any substrate topology issues! (4/5)

The complex that recycles these SNAREs is called NSF/Sec18. However, our mehanistic understanding of how these complex SNARE proteins are pulled through the NSF/Sec18 complex is poor. SNAREs are like a knotted thread that must somehow be threaded by a NSF/Sec18 needle (3/5)

SNARE proteins are the engines for membrane fusion; they cause neurotransmitters to be released in a synpatic cleft all the way to the relase of hormones. After these SNAREs perform their job, they must naturally be recyled and prepared for additional rounds of fusion (2/5)