International audienceIn this presentation, I will share our recent work on two modification reactions that are catalysed through a new paradigm. This paradigm involves a composite active site composed of catalytic residues from two different proteins. First, I will talk about how PARP1, a well-characterised ADP-ribosylating enzyme, is complemented by the protein cofactor HPF1. HPF1 is required for recognising and activating a serine residue in a protein substrate. In the second part, I will discuss an analogous interaction between DELTEX E3 ligases and E2 enzymes in catalysing a novel ubiquitylation reaction on a hydroxyl group of an ADP-ribose moiety. The talk will highlight chemical and mechanistic analogies between different modification reactions.References:[1] MJ Suskiewicz, F Zobel, T Ogden, …, D. Neuhaus, I. Ahel, Nature, 2020, 579, 598-602[2] K Zhu, MJ Suskiewicz, …, V. Aucagne, D. Ahel, I. Ahel, Sci Adv, 2022, 8(40):eadd425