Magnus Wolf-Watz lab

Protein dynamics is in essence the plasticity that proteins display when they change their shape in order to perform their biological function. Understanding the mechanisms and energetics that control dynamics is currently at the fore-front of contemporary research in protein chemistry.

In my lab protein dynamics is addressed in systems of varying complexity spanning from individual enzymes to complex biological systems and designed protein switches. The main technique in the lab is solution state NMR spectroscopy which is the most powerful approach to quantify protein dynamics that can cover the entire range from fast (ps-ns) to slow (seconds to minutes) events. We use the full spectrum of structural biology techniques including: xray-crystallography, molecular dynamics simulations and single particle cryoEM. In all projects we carefully design functional assays that are used to connect protein dynamics with biological function.

Research directions

Structural enzymology

Here we focus on fundamental linkages between dynamics and enzymatic catalysis.  The main focus has been on the metabolic enzyme adenylate kinase isolated from organisms in all domains of life. In the research program we have contribute by identifying several new meninism’s such as the geometrical role of the magnesium ion for phosphoryl group transfer (DOI: 10.1126/sciadv.ado5504). Within the project we have now initiated studies on the enzyme cocoonase that is key for the ability of the silk moth to escape from its cocoon and also the human protein kinase Aurora B that is linked to several forms of human cancer. Key collaborators are Elisabeth Sauer-Eriksson lab at Umeå University and Kwangho Nam at the University of Texas at Arlington, USA.

Infection biology

Here we focus on a select set of proteins that are key for the infectivity of Yersinia pseudotuberculosis through the type III secretion system (T3SS). In a collaboration with Matthew Francis lab at umeå University we can connect conformational dynamics in protein with the ability of Yersinia to secrete effector proteins (Yop’s) through the T3SS system. We have previously shown that protein dynamics manifested as dissociation of the heterodimeric protein, YscU, is an important step in the process of Yop secretion (doi.org/10.1371/journal.pone.0049349).

Design and directed evolution

In our newest research direction, we are studying the underlying mechanisms that enable designed protein-switches to function. The direction is a collaboration with Sophia Hober lab at KTH, Sweden. Hober and co-workers has through directed evolution with alternating positive and negative selection pressures developed proteins that binds a target-protein only in the presence of calcium ions. We have now in collaboration with the Hober lab shown that one such protein switch functions by mimicry of a naturally evolved mechanism. Through NMR we demonstrated that a binding surface that is disordered in the absence of calcium becomes ordered and activated when coordinating a calcium ion. The mechanism described in JBC (DOI: 10.1016/j.jbc.2024.107795) has been denoted “coupled folding and binding” in the evolution of natural proteins. We now continue to search for additional fundamental mechanisms in other protein-switches with the aim to define general rules in protein design.