izvor podataka: poirot

Naziv

Aminoacil-tRNA-sintetaze kao čuvari standardnog genetičkog koda

Aminoacyl-tRNA synthetases as gatekeepers of the standard genetic code

Opis projekta

Genetički kod definira zakonitosti koje omogućavaju prevođenje genetičke informacije u funkcionalne molekule proteina. Suodnos kodona i aminokiseline ostvaruje se pomoću aminoacil-tRNA-sintetaza (aaRS), enzima koji sparuju aminokiselinu s pripadnom molekulom tRNA. Visok stupanj točnosti u translaciji osigurava se dijelom kroz korektivne mehanizme enzima aaRS. Učestalost mistranslacije predstavlja važno pitanje u temeljnim istraživanjima i njihovoj primjeni u medicini i biotehnologiji. Korektivni mehanizmi također djeluju kao čuvari standardnog genetičkog koda i sprječavaju ugradnju prirodnih aminokiselina koje nisu definirane genetičkim kodom. Ti mehanizmi, s druge strane, mogu otežati ugradnju sintetskih aminokiselina u dizajnerske proteine. U sklopu projekta predlaže se istraživanje sintetskih i korektivnih mehanizama enzima koji omogućuju ugradnju leucina, valina i izoleucina u proteine. Usporedit ćemo katalitičke principe i specifičnost sintetskog i korektivnog mjesta tih enzima prema proteinogenim aminokiselinama i onima koje nisu kodirane genetičkim kodom. Također, istražit ćemo toksičnost mistranslacije i stanični odgovor na izazvani stres. Cilj je razumjeti principe koji definiraju odabir standardne aminokiselinske abecede te kako narušavanje genetičkog koda utječe na staničnu fiziologiju. Navedene spoznaje olakšat će usmjerenu ugradnju fluoriranih aminokiselina u dizajnerske proteine. Konačno, testirat ćemo postojanje sprege između točnosti translacije i adaptacije na stres izazvan okolišnim uvjetima. Ovo istraživanje, kroz redizajniranje suodnosa kodona i aminokiseline, nalazi se na granici biokemije i kemijske biologije. Atraktivnost i izvedivost predloženog istraživanja uočljiva je kroz suradnje naše grupe, značajno prepoznate u polju biosinteze proteina, s istaknutim internacionalnim (Prof. Budiša, TU Berlin, Prof. Anderluh, NIC, Ljubljana, Prof. Maček, Proteome Center Tübingen) i domaćim (Dr. Vianello, IRB, Zagreb) partnerima.

The genetic code provides the basis for translation of genetic information into functional proteins. Codon assignments are established by aminoacyl-tRNA synthetases (aaRS), which couple amino acids to their cognate tRNAs. Mistakes in translation are generally kept low, in part by inherent aaRS hydrolytic editing. The extent to which mistranslation occurs presents a fundamental question in basic research with impact on medicine and biotechnology. AaRS quality control mechanisms also act as gatekeepers of the standard genetic code and prevent infiltration of natural but non-coded amino acids. Consequently, they present an obstacle for synthetic amino acid translation in rational protein design. Here we propose to investigate the synthetic and editing mechanisms of three aaRSs responsible for translation of amino acids that build the protein core: leucine, valine and isoleucine. We will compare the catalytic principles and gained specificity of the enzymes’ synthetic and editing sites against proteinogenic and non-coded amino acids. The cellular toxicity and stress responses of induced non-canonical mistranslation will be addressed. The goal is to improve our understanding of the basis for selection of the natural amino acid alphabet, and how violation of the coding principles influences cell physiology. Mechanistic insight will extend our ability to apply fluorinated amino acids in protein rational design. A possible link between altered translational fidelity and adaptation to environmental stress will be sought. This research couples biochemistry and chemical biology through the interest in reassignment of the genetic code. The assembled expertise through the international (Prof. Budiša, TU Berlin, Prof. Anderluh, NIC, Ljubljana, and Prof. Maček, Proteome Center Tübingen) and national (Dr. Vianello, RBI, Zagreb) collaborators will strongly enhance the capacity of our group, which is well-recognized in the field of protein translation, to conduct this research.

Ključne riječi

aminoacil-tRNA sintetaze, biosinteza proteina, translacijska kontrola kvalitete, norvalin, sintetske aminokiseline, uređivanje

aminoacyl-tRNA synthetases, protein biosynthesis, translational quality control, norvaline, synthetic amino acids, editing

Znanstveno-istraživački projekti

AARSCODE

IP-2016-06-6272

01.03.2017

31.08.2021

nije evidentirano

HRK 1.000.000,00

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