Mechanobiology
Protein conformation can be modulated in response to chemical and physical stimulus arising from interactions with other molecules and as result of chemical modifications. The Protein Dynamics group uses state of the art experimental and computational methods to elucidate the relations between protein conformation and function. One of the focus points of our studies involves the structural dynamics of the proteins in cellular adhesion sites. In particular, we aim for a more complete understanding of the mechanisms behind cellular mechanosensing. The tools and techniques used in our studies involve cellular models, tailored hydrogel substrates for cell adhesion studies, protein engineering and molecular dynamics simulations. Collaborations with the University of Geneva and the Imperial College of London are essential for the project.

Vaccine development
Enteroviruses are responsible for symptoms ranging from mild respiratory illnesses, such as common cold, to more severe conditions, such as neonatal sepsis-like disease and acute flaccid paralysis. In the genus of Enteroviruses, vaccines are currently available only against the poliovirus. We are developing novel diagnostic tools and vaccines against enteroviruses, with a focus on virus forms associated with type 1 diabetes. Our project is conducted in close collaboration with the Karolinska Institutet.

Methodology
We utilize a broad set of biophysical characterization methods, including calorimetry, biosensors and spectroscopic methods. Recombinant proteins and protein engineering are used routinely in our research and our gained expertise is geared towards the development of novel biofunctionalized materials, including nanocellulose and bioactive glass.

Our group is active within Biocenter Finland infrastructure network (About research infrastructure / Biocenter Finland).

Researchgate (laboratory): Hytonens-lab
Researchgate (profile): Vesa_Hytönen

Recent results

StructureMapper algorithm

The StructureMapper algorithm provides automated, high-throughput mapping of primary sequence amino acids to existing three-dimensional protein structures in the PDB database. The StuctureMapper analyzes the properties of the identified structural locations (e.g. surface accessibility) and can construct any defined biological assemblies for proteins to identify amino acids located at protein-protein interfaces (PPIs). In our study, we have used the StructureMapper to profile the structural locations of 354 781 post-translational modifications sites and to discover novel, potential phosphoswitches.

Nurminen et al.
StructureMapper: a high-throughput algorithm for analyzing protein sequence locations in structural data
Bioinformatics, 2018

https://doi.org/10.1093/bioinformatics/bty086

Note: This article is available under theCreative Commons CC-BY-NC https://creativecommons.org/licenses/license and permits non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.

New monoclonal enterovirus antibody

Enteroviruses are a group of RNA viruses that frequently infect humans, with symptoms varying from a mild rash to paralytic poliomyelitis. While enteroviruses are common, there are only a handful of reliable methods for their detection and identification. In this study, we describe a new monoclonal antibody, 3A6, which detects a broad range of enteroviruses and works in multiple applications.

Saarinen et al.
A novel rat CVB1-VP1 monoclonal antibody 3A6 detects a broad range of enteroviruses.
Sci. Rep. 2018, 8(1):33

https://www.nature.com/articles/s41598-017-18495-4

Protein interplay in atherosclerosis

Increased expression of histone deacetylase 9 (HDAC9) and matrix metalloprotease 12 (MMP12) in carotid artery wall has been linked to the development of atherosclerosis and adverse clinical outcome of its treatment. Here, we utilized genome-wide expression analysis to study the association of MMP12 and HDAC9 expression in atherosclerotic plaques with plaque stability and with macrophage and smooth muscle cell markers. We found an association of HDAC9 and MMP12 expression in carotid artery plaques and identified M4 macrophages as a possible source of the increased MMP12 and HDAC9 expression in these plaques. Immunohistochemistry of tissue sections from artery plaques and healthy arteries confirmed colocalization of HDAC9 and MMP12 signals with each other and with the macrophage markers. These results suggest that M4 macrophages may play an important role in the development and progression of atherosclerotic plaques in arteries.

Oksala et al.
Synergistic Expression of Histone Deacetylase 9 and Matrix Metalloproteinase 12 in M4 Macrophages in Advanced Carotid Plaques.
Eur. J. Vasc. Endovasc. Surg. 2017, 53(5), 632-640

http://www.sciencedirect.com/science/article/pii/S1078588417301259

Talin stability influences cellular functions

Force-controlled unfolding of a central cell-matrix adhesion protein called talin has been suggested to act as a cellular mechanosensor, but so far the effects of talin destabilization have not been studied. In this study, we designed a panel of point mutations destabilizing a mechanosensitive subdomain in talin rod and analyzed the phenotypes induced by them in cultured fibroblast cells. Talin destabilization was found to affect adhesion protein dynamics, cell migration rate and ECM substrate sensing. These results provide evidence into how the controlled talin rod domain unfolding acts as a key regulator of adhesion structure and function in adherent animal cells.

Rahikainen et al.
Mechanical stability of talin rod controls cell migration and substrate sensing.
Scientific Reports 2017, 7, 3571

https://www.nature.com/articles/s41598-017-03335-2.epdf

Novel coxsackievirus vaccine

Vaccination would be powerful tool to prevent CVB associated diseases. We developed an efficient vaccine production protocol for CVB vaccines by optimizing virus production, purification and formulation steps. Administration of formalin-inactivated CVB1 induced a strong, virus-neutralizing antibody response in vaccinated mice, and protected mice against CVB1 infection. Altogether, these results provide valuable information for the development of new enterovirus vaccines for human use.

Hankaniemi et al.
Optimized production and purification of Coxsackievirus B1 vaccine and its preclinical evaluation in a mouse model Vaccine. 2017

Free access to full article: https://authors.elsevier.com/a/1VBag,60n7SQ~j

Article: www.sciencedirect.com

Stretching of talin rod

Using single-molecule atomic force microscopy (smAFM), we show that the entire talin rod can be unfolded by mechanical extension, over a physiological range of forces between 10 and 40 pN. We also demonstrate, through a combination of smAFM and steered molecular dynamics, that the different bundles within the talin rod exhibit a distinct hierarchy of mechanical stability. These results provide a mechanism by which different force conditions within the cell control a graduated unfolding of the talin rod. Mechanical unfolding of the rod subdomains, and the subsequent effect on talin’s binding interactions, would allow for a finely tuned cellular response to internally or externally applied forces.

Haining et al.

All Subdomains of the Talin Rod Are Mechanically Vulnerable and May Contribute To Cellular Mechanosensing.

ACS Nano. 2016, 10(7), 6648-58.
http://pubs.acs.org/doi/abs/10.1021/acsnano.6b01658

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