Aarhus Universitets segl

Magnus Kjærgaard

The protein structure-function paradigm has served as the basis for understanding of how proteins work for 70 years. However, it is increasing clear that many proteins are functional despite not having any structure at all. We now know that functional proteins can fall anywhere in the continuum from rock-solid to completely disordered. My research centers on proteins in the dynamic and disordered protein end of that spectrum. The over-arching research question that drives our group is thus to understand how intrinsically disordered proteins control cellular signaling and protein trafficking in neurons. This work has inspired our efforts not only to study natural proteins, but also to engineer new proteins with functions unknown in nature.

Our lab is mainly an experimental protein biochemistry and biophysics lab. We are well equipped to make proteins in a range of expression systems and characterize their structure, function, interactions, and assembly using chemical and physical methods. I also act as the scientific coordinator of the department’s “Biophysics and Biochemistry Core Facility”, and we use advanced instruments a lot. Our lab also uses primary neurons from rodents and model cell lines – typically in combination with microscopy techniques. Finally, I have a weakness for mathematical modelling and like to describe biochemical systems with either analytical or numerical models.

Design principles of intrinsically disordered proteins

Intrinsically disordered proteins are often most productively understood via a sequence-function relationship, where functions are driven by either short linear motifs or the global physical and chemical properties of the chain. We aim to understand such relationships in order to understand the roles of disordered proteins in biology – and to engineer new proteins for applications in medicine and biotechnology. Our strategies often involve minimalistic model systems, where sequence-function relation ships can be discerned through systematic variation. Currently, we study:

Enzyme tethers: Many enzymes are enhanced by targeting domains or exosites that recruit the substrate to the vicinity of the catalytic site. We develop quantitative models that describe how disorder linkers affect such intra-complex reactions in signaling pathways.

Desiccation chaperones: Extreme-tolerant organisms have developed a class of intrinsically disordered proteins that protect their cells against desiccation, freezing and other stressors. We study such proteins to learn how their protective mechanism can be used to preserve biopharmaceuticals.

Metal binding motifs: Many IDPs bind metal-ions through short linear peptide motifs, which contribute to the pathological mechanism in e.g. Alzheimer’s disease. We aim to understand the sequence grammar and biophysics of such interactions.

Biomolecular condensates

Cells are divided into compartment with different functions. In addition to the traditional membrane-bounded organelles, it has recently been discovered that there are another class of “membrane-less organelles” that arise due to reversible self-assembly of macromolecules. Intrinsically disordered proteins play a key role in formation of such biomolecular condensates. We study the effects of biomolecular condensates particularly on enzymatic reactions, which can be dramatically increase or decreased when transferred into a condensate. Currently, we focus on two different types of enzymatic systems:

Signaling pathways: Kinases and phosphatases are the backbone of cellular signaling. Many signaling enzymes are found in biomolecular condensates, but we know little of how the environment of the condensate affects their activities. Understanding such effects are crucial to the emergent class of pharmaceuticals that aim to modulate biomolecular condensates.

Biosynthetic pathways: Nature has created a treasure trove of organic compounds with potential applications in medicine and industry. Many of these compounds are too rare to extract from natural sources and has to be created in a lab – typically in genetically engineered microorganisms. However, many biosynthetic pathways work poorly when transplanted to e.g. yeast or bacteria. We aim to develop biomolecular condensates as “designer organelles” for biosynthesis pathways of complex natural compounds.

Targeting of synaptic proteins in memory

Targeting of synaptic proteins in memory

How are memories stored in out brains? This is the central question in the Center of Excellence PROMEMO of which we are part. Decades of research in molecular neuroscience has shown that activity-dependent changes in synaptic strengths and connections are the cellular and molecular underpinning. This strengthening requires that the molecular machinery of neurotransmission is recruited to specific synapses in response to the biochemical activity triggered by synaptic stimulation. But how do these mechanisms work at the molecular level?  Unsurprisingly, intrinsically disordered proteins seem to play a key role. We aim to answer this question by studying:

Disordered tails of neuronal receptors: Many crucial neuronal receptors have long disordered tails that are not part of their main receptor function, but rather regulate their location, interactions and signaling output. We study such receptor tails in vitro and in cells.

Reverse engineering activity dependent protein recruitment: Imagine if we could target any protein to a synapse in response to synaptic stimulation. This is what we are trying to achieve by reverse engineering the mechanisms neurons use to target proteins to the right synapses.

We are also part of the Danish Research Institute of Translational Neuroscience (DANDRITE) - the Danish node of the EMBL partnership.

Peer-reviewed publikationer

Sortér efter: Dato | Forfatter | Titel