![]() ![]() 10 During post-translational modification, the full-length protein is cleaved at the end of the N-terminal signaling domain concomitantly, the last residue of the N-terminus is released as a cholesterol ester. The initially translated, full-length Hh proteins (typically 350-475 residues in length) consist of an N-terminal signaling domain, an internal catalytic domain, and a C-terminal region known as the Sterol Recognition Region (SRR, Fig. ![]() ![]() 5, 6 This unique modification appears to have co-evolved with cholesterol-sensing mechanisms that coordinate Hh signal transduction, chemically linking embryogenesis to cholesterol homeostasis. 2 Cholesterol modification is fundamental to the activity of the Hh morphogen 3, 4 mutation of the catalytic residues are lethal, and mutations that reduce the efficiency of the reaction give rise to profound congenital disorders (Fig. 1 To date, this intramolecular small molecule transfer activity has been observed only in Hh proteins and in no other domains of life. The Hedgehog (Hh) morphogens undergo an auto-catalytic modification that cleaves the translated protein approximately in half and covalently appends cholesterol to the last residue of the N-terminal fragment. Our investigations offer the first functional template of this region, providing opportunities to identify parallel reactivity in nature and revealing new mechanisms that can be exploited as tools in chemical biology. We use a combination of sequence conservation, directed mutagenesis, and biochemical assays to specify residues of the SRR that are responsible for cellular and biochemical processes in Hh cholesterolysis. To elucidate the chemical mechanism of this modification, we have defined roles of the uncharacterized sterol recognition region (SRR) in Hh proteins. The isoform- and context-specific efficiency of the ligation reaction has profound impact on the activity of Hh morphogens and represents an unexplored aspect of Hh ligand-dependent cancers. One such example occurs in the Hedgehog (Hh) morphogens, proteins singular across all domains of life for the nature of their covalent ligation to cholesterol. In metazoans, there exist rare chemical modifications that occur through entirely unique mechanistic regimes. “(It’s) the one I’m most proud of putting out, mainly because I think it’s where my vocal cadence shines the most.Nature provides a number of mechanisms to encode dynamic information in biomolecules. While the music is an essential piece, a good collective happens to come from being good friends.” Kuru cites “Typo”, an otherworldly fusion of UK drill and Europop sounds, as a personal favourite among his tracks to date. “The outside world only really sees our music, but a lot of times we just sit inside and play video games all day. “So I went out and tried to pursue it myself.” Citing his closest friends and fellow hyperpop artists blackwinterwells, d0llywood1 and 4am as vocal inspirations, kuru has developed his sound as part of the wider community groups NOVAGANG and bloodhounds. “The reason I started making music was because I heard this one demxntia song and got mesmerised by how someone could do that in their room,” he says. KURUįifteen-year-old kuru, who lives an hour from Washington DC, is stretching the sonic possibilities of the already-expansive hyperpop scene. Once you’re there, it’s hard to turn back. In “Astrid”, a single that lasts just one minute and 42 seconds, he takes us to the “ forest on the east side where all the evil beasts lie / And I cannot deny that my brain buzzin’ like a beehive”. “I never had any plans to make hyperpop-type music or to emulate 100 gecs.” Like the first-player games he is often immersed in, glaive’s songs paint a world of open fields and forests, inspired by the expansive landscapes around his hometown of Hendersonville. “I didn’t really have an inclination towards the genre, I just liked a bunch of artists in the scene,” he says. His dizzying and hook-laden tracks sound like they’ve happened almost by accident, but they have come to define the new musical era of hyperpop. He began making music towards the start of the pandemic and, by the end of 2020, had released his debut EP, Cypress Grove, via Interscope along with a flurry of emotionally charged, digitised pop singles. In the static suburbia of North Carolina, 16-year-old glaive AKA Ash Gutierrez is nestled between hives of Discord servers and video-game pause screens.
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