I am trained as an organic/medicinal chemist and nowadays take advantage of chemistry in combination with chemical biology techniques to interrogate the complex Ubiquitin Proteasome System (UPS). Post-translational modification of proteins with ubiquitin (Ub) is a dynamic process that regulates nearly every single cellular process. A cascade of E1, E2, E3 enzymes is responsible for the defined conjugation of a Ub to a substrate, whereas removal of the Ub is regulated by proteases termed deubiquitylating enzymes (DUBs). I developed a novel activity-based probe (ABP) to study substrate context in the monitoring of DUB activity, the first ligase probe that can travel and trap the full conjugation machinery and more recently ABPs based on ubiquitin-like proteins. Complementing this, I initiated a new line of research investigating the role of the UPS in neurodegeneration. Utilizing both activity-based probes as well as biochemistry and cell biology techniques, I am currently seeking to unravel the role of ubiquitination and the proteasome in neurodegeneration. The aim of our research is to discover unique components of the UPS that could become therapeutic targets in the future.
I received my MSc. with honors in Chemical Sciences from Utrecht University in 2007. I started my doctoral studies at the division Medicinal Chemistry in Utrecht University studying the design and synthesis of a novel class of macrocyclic antifungal peptides. I obtained my PhD degree in 2012 and joined the group of Prof. Dr. Huib Ovaa at the NKI as a postdoc. I moved to the LUMC in 2016 and hold a staff senior research scientist position. In 2018 I obtained a Huntington Stimulation Grant from the Dutch Vereniging van Huntington and a ZonMW OffRoad grant to study the UPS in Huntington’s Disease.
A cascading activity-based probe sequentially targets E1-E2-E3 ubiquitin enzymes.
Mulder MPC, Witting K, Berlin I, Pruneda JN, Wu KP, Chang JG, Merkx R, Bialas J, Groettrup M, Vertegaal AC, Schulman BA, Komander D, Neefjes J, El Oualid F, Ovaa H.
Nat Chem Biol. 2016 Jul;12(7):523-30.
Molecular basis of Lys11-polyubiquitin specificity in the deubiquitinase Cezanne.
Mevissen TET, Kulathu Y*, Mulder MPC*, Geurink PP, Maslen SL, Gersch M, Elliott PR, Burke JE, van Tol BDM, Akutsu M, Oualid FE, Kawasaki M, Freund SMV, Ovaa H, Komander D.
Nature. 2016 Oct 20;538(7625):402-405.
Total Chemical Synthesis of SUMO and SUMO-Based Probes for Profiling the Activity of SUMO-Specific Proteases.
Mulder MPCǂ, Merkx R, Witting KF, Hameed DS, El Atmioui D, Lelieveld L, Liebelt F, Neefjes J, Berlin I, Vertegaal ACO, Ovaa Hǂ.
Angew Chem Int Ed Engl. 2018 Jul 16;57(29):8958-8962.