MOLECULAR MECHANISMS OF DISEASES

MOLECULAR MECHANISMS OF DISEASES

MOLECULAR MECHANISMS OF DISEASES

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RESEARCH


We are interested in how cellular functions are mediated at molecular level, via interactions between proteins, and by response on external mechanical forces. Short descriptions of current projects are given below.

In our work we apply various structural biology techniques such as X-ray crystallography, NMR-spectroscopy, SAXS, as well as theoretical biophysics approaches such as MD and SMD simulations.

PROJECTS

Molecular Mechanisms of Diseases Associated to Filamin

Filamins (FLNs) are actin crosslinking proteins. FLNs form a homodimeric structure (dimerization occurs at domain 24), presenting an amino terminal actin-binding domains, followed by a chain of 24 immunoglobulin domains. Three FLN coding genes are found in humans: X-chromosomal FLNA, and autosomal FLNB and FLNC. Various mutations, small deletions or insertions, truncating nonsense mutations and missense mutations have been characterized in all three FLN encoding genes.Mutations in FLNs are linked to a diverse array of congenital disorders influencing the development of central nervous system, cardiovascular system, muscle and connective tissue. The mutations span throughout the proteins, but disease-specific clustering of mutations are observed.

In this project, our aim is to learn to understand the molecular mechanisms behind FLN associated diseases. Currently, we constentrate in skeletal dysplasias as well as mitral valve prolapse. In our research we combine various structural biology techniques such as X-ray crystallography, NMR-spectroscopy and SAXS with other biochemical and biophysical techniques such as CD-spectroscopy.

Collaborators

Prof. Perttu Permi, Department of Biological and Environmental Science, University of Jyväskylä

Prof. Jean Merot, University de Nantes, France

Publications
Jonne Seppälä, Rafael C. Bernardi, Tatu Haataja, Maarit Hellman, Olli T. Pentikäinen, Klaus Schulten, Perttu Permi, Jari Ylänne & Ulla Pentikäinen
Skeletal Dysplasia Mutations Effect on Human Filamins’Structure and Mechanosensing
Sci Rep. 2017 Jun 26;7(1):4218.



Mechanosensing

Cells explore their environment by sensing and responding to mechanical forces. Fundamental cellular processes, such as cell migration, differentiation, and homeostasis, take advantage of this sensing mechanism. At molecular level mechanosensing is mainly driven by mechanically active proteins. These proteins are able to sense and respond to forces by, e.g., undergoing conformational changes exposing cryptic binding sites or even by becoming more tightly bound to one another. Defective responses to forces are known to cause a plethora of pathological conditions, including cardiac failure, as well as pulmonary injury and are also linked to cancer.

In this project, we study how shear forces applied to cytoskeletal protein Filamin influece Filamin's structure and function. To investigate force induced structural changes, we use theoretical biophysical approach, called steered molecular dynamics (SMD) simulations.

Collaborators

Prof. Klaus Schulten and Ph.D. Rafael Bernardi in Theoretical and Biophysical Group, University of Illinois at Urbana Champaign, USA



Publications
Jonne Seppälä, Rafael C. Bernardi, Tatu Haataja, Maarit Hellman, Olli T. Pentikäinen, Klaus Schulten, Perttu Permi, Jari Ylänne & Ulla Pentikäinen
Skeletal Dysplasia Mutations Effect on Human Filamins’Structure and Mechanosensing
Sci Rep. 2017 Jun 26;7(1):4218.

Ulla Pentikäinen ja Jari Ylänne
The regulation mechanism for the auto-inhibition of binding of human filamin A to integrin
Journal of Molecular Biology, 2009, 393, 644-657

There is a Pro Gradu position available in this project. OPEN POSITIONS


Cancerous PP2A inhibitors

Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. Why normal cells are transformed to cancer cells is not completely understood. However, it is evident that defects in balance of reversible protein phosphorylation pathways contribute to cancer. Protein phosphatase 2A (PP2A) is one of various phosphatases in cell and a key player in well-balanced reversible protein phosphorylation. Recently, several PP2A inhibitor proteins have been identified in cancer cells. Accordingly targeting of endogenous PP2A inhibitory proteins may be an effective approach for cancer therapy.

The aim of this project is to investigate three recently identified cancerous PP2A inhibitor proteins. These all are potential novel anticancer targets related e.g to breast cancer and glioblastoma multiforme. In this project, we will first reveal the atomic detailed structure for one of PP2A inhibitor proteins, the structure of which is currently unknown. For this, X-ray crystallography and/or NMR-spectroscopy will be used. Next, by using X-ray crystallography, our aim is to determine the complex structures for certain cancerous PP2A inhibitors with molecules that inhibit their binding to PP2A.

Collaborators

Prof. Jukka Westermarck, Turku Centre for Biotechnology, Finland

Prof. Perttu Permi, Department of Biological and Environmental Science, University of Jyväskylä

Docent Olli Pentikäinen, University of Jyväskylä, Finland


OPEN POSITIONS

STRUCTURES

X-ray structures


FLNa20-21

FLNa20-21 in complex with migfilin peptide

PDB CODE:4P3W

FLNb16-17

FLNb16-17

PDB CODE:5DCP



FUNDING

Academy of Finland Research Fellowship for the project "The regulation mechanisms of filamins’ physiological functions"



PEOPLE


Principal Investigator

Ulla Pentikäinen, Ph.D. Academy Research Fellow/University lecturer
contact: ulla.m.pentikainen'at'jyu.fi

Post docs

Tatu Haataja, Ph.D.

Ph.D. students

Chandan Thapa
Sanna Rauhamäki

Master students

Ellanoora Martikainen

Researcher assistant

Sami Salmikangas Pekka Roivas

Alumni

Bachelor students
Emma Viitala
Elina Hurskainen
Iida Koskela

OPEN POSITIONS


Pro Gradu paikka

Kuinka solun tukirangan voima välittyy aktiinista solukalvolle?

Mekaanisilla voimilla on suuri merkitys biologisissa systeemeissä. Solut tuntevat ja vastaavat ympäristön mekaanisiin signaaleihin esimerkiksi muuntamalla geenien ilmenemistä, muuntamalla solun ulkopuolista matriisia tai esimerkiksi ilmentämällä erilaisia biokemiallisia aktiivisuuksia. Molekyylitasolla näitä tehtävistä vastaavat mekaanisesti aktiiviset proteiinit, joidenka voiman vaikutuksesta kolmiulotteinen rakenne muuttuu voiman vaikutuksesta. Tällöin esimerkiksi voi paljastua uusille proteiineille sitoutumispaikkoja mikä saa aikaan signaalin välityksen muuttumisen solussa. Solun voimanvälityksen viallinen toiminta aiheuttaa monia sairauksia kuten sydän- ja verisuonitauteja, kehityshäiriöitä ja syöpää. Solujen voimanvälitysmekanismit ovat vielä erittäin huonosti tunnettuja, johtuen siitä, että niiden tutkiminen on erittäin haasteellista.

Tässä pro gradu -työssä on tavoitteena tutkia kuinka solun tukirangan Filamiini-proteiini välittää mekaanisia voimia aktiinista solukalvolle. Työssä käytetään laskennallisen fysiikan menetelmää ”steered molecular dynamics simulation”. Gradulaiselta ei vaadita aikaisempaa kokemusta laskennallisen biofysiikan menetelmistä. Proteiinien rakenna ja toiminta kurssi olisi hyvä olla suoritettuna tai muuten omata vastaavat tiedot.

Tiedustelut:
ulla.m.pentikainen'at'jyu.fi

Publications


Please note that before year 2005 Kaukinen, after Pentikäinen

Peer-reviewed scientific articles

* equal contribution

Jonne Seppälä, Rafael C. Bernardi, Tatu Haataja, Maarit Hellman, Olli T. Pentikäinen, Klaus Schulten, Perttu Permi, Jari Ylänne & Ulla Pentikäinen
Skeletal Dysplasia Mutations Effect on Human Filamins’Structure and Mechanosensing
Sci Rep. 2017 Jun 26;7(1):4218.

Jonne Seppälä, Helena Tossavainen, Neboja Rodic, Perttu Permi, Ulla Pentikäinen*, Jari Ylänne*
Flexible Structure of Peptide Bound Filamin A Mechanosensor Domain Pair 20-21
PLoS One, 2015, 10(8):e0136969

Ritika Sethi, Jonne Seppälä, Helena Tossavainen, Mikko Ylilauri, Salla Ruskamo, Olli Pentikäinen, Ulla Pentikäinen, Perttu Permi, Jari Ylänne
A Novel Structural Unit in the N-terminal Region of Filamins
Journal of Biological Chemistry, 2014, 289, 8588-8598

Mikko Ylilauri, Elina Mattila, Elisa M. Nurminen, Jarmo Käpylä, Sanna P. Niinivehmas, Juha A. Määttä JA, Ulla Pentikäinen, Johanna Ivaska, Olli T. Pentikäinen
Molecular mechanism of T-cell protein tyrosine phosphatase (TCPTP) activation by mitoxantrone
Biochim Biophys Acta 2013,1834, 1988-1997

Salla Ruskamo, Robert Gilbert, Gregor Hofmann, Pengju Jiang, Iain D. Cambell, Jari Ylänne, Ulla Pentikäinen
The C-terminal rod 2 fragment of filamin A forms a compact structure that can be extended
Biochemical Journal, 2012, 446, 261-269

Ulla Pentikäinen, Pengju Jiang, Heikki Takala, Salla Ruskamo, Iain D Campbell, Jari Ylänne
Assembly of a Filamin Four-domain Fragment and the Influence of Splicing Variant-1 on the Structure
Journal of Biological Chemistry, 2011, 286, 26921-26930

Elisa Nurminen, Marjo Pihlavisto, László Lázár, Ulla Pentikäinen, Ferenc Fülöp, Olli Pentikäinen
Novel Hydrazine Molecules as Tools To Understand the Flexibility of Vascular Adhesion Protein-1 Ligand-Binding Site: Toward More Selective Inhibitors
Journal of Medicinal Chemistry, 2011, 54, 2143-2154

Elisa Nurminen, Marjo Pihlavisto, László Lázár, Zsolt Szakonyi, Ulla Pentikäinen, Ferenc Fülöp, Olli Pentikäinen
Synthesis, in vitro activity, and three-dimensional quantitative structure-activity relationship of novel hydrazine inhibitors of human Vascular Adhesion Protein-1
Journal of Medicinal Chemistry, 2010, 53, 6301-6315

Ulla Pentikäinen ja Jari Ylänne
The regulation mechanism for the auto-inhibition of binding of human filamin A to integrin
Journal of Molecular Biology, 2009, 393, 644-657

Ulla Pentikäinen, Katherine Shaw, Kittusamy Senthilkumar, Christopher Woods, Adrian Mulholland
Lennard-Jones parameters for B3LYP-CHARMM27 QM/MM modelling of Nucleic Acid Bases
Journal of Chemical Theory and Computation, 2009, 5, 396-410

Ulla Pentikäinen, Olli T. Pentikäinen, Adrian J. Mulholland
Cooperative symmetric to asymmetric conformational transition of the apo-form of scavenger decapping enzyme revealed by simulations
Proteins, Structure, Function and Bioinformatics, 2008, 70, 498-508

Fumiko Marttila-Ichihara, David J. Smith, Craig. Stolen, Gennady. Yegutkin, Kati. Elima, Nathalie. Mercier, Marika Merinen, Riku Kiviranta, Marjo Pihlavisto, Sakari Alaranta, Ulla Pentikäinen, Olli T. Pentikäinen, Ferenc Fülöp, Sirpa Jalkanen, Marko Salmi
Vascular amine oxidases are needed for leukocyte extravasation into inflamed joints in vivo.
Arthritis & Rheumatism, 2006, 54, 2852-62.

James M. Sanders, Olli T. Pentikäinen, Luca Settimo, Ulla Pentikäinen, Muneo Shoji, Makoto Sasaki, Ryuichi Sakai, Mark S. Johnson, and Geoffrey T. Swanson
Determination of binding site residues responsible for the subunit selectivity of novel marine-derived compounds on kainate receptors.
Molecular Pharmacology, 2006, 69, 1849-1860.

Ulla Pentikäinen, Luca Settimo, Mark S. Johnson, Olli T. Pentikäinen
Subtype selectivity and flexibility of ionotropic glutamate receptors upon antagonist ligand binding.
Organic and Biomolecular Chemistry, 2006, 4, 1058-1070

Teija Niittymäki, Ulla Kaukinen, Pasi Virta, Satu Mikkola, Harri Lönnberg
Preparation of azacrown functionalized 2´-O-methyl oligoribonucleotides, potential artificial RNases
Bioconjugate Chemistry, 2004, 15, 174-184.

Ulla Kaukinen, Harri Lönnberg, Mikael Peräkylä
Stabilisation of the transition state of phosphodiester bond cleavage within linear single-stranded oligoribonucleotides
Organic and Biomolecular Chemistry, 2004, 2, 66-73.

Ulla Kaukinen, Tuomas Venäläinen, Harri Lönnberg, Mikael Peräkylä
The base sequence dependent flexibility of linear single-stranded oligoribonucleotides correlates with the reactivity of the phosphodiester bond
Organic and Biomolecular Chemistry, 2003, 1, 2439-2447

Ulla Kaukinen, Sari Lyytikäinen, Satu Mikkola, Harri Lönnberg
The reactivity of phosphodiester bonds within linear single-stranded oligoribonucleotides is strongly dependent on the base sequence
Nucleic Acids Research, 2002, 30, 469-474.

Ulla Kaukinen, Lukasz Bielecki, Satu Mikkola, Ryszard W. Adamiak, Harri Lönnberg
The cleavage of phosphodiester bonds within small RNA bulges in the presence and absence of metal ion catalysts
Journal of Chemical Society, Perkin Transactions 2, 2001, 1024-1031.

Mohamed I. Elzagheid, Esa Mäki, Ulla Kaukinen, Mikko Oivanen, Harri Lönnberg
Preparation, hydrolysis and intramolecular transesterification of 3'-deoxy-3'-thioinosine 3'-S-dimethylphosphorothiolate
Nucleosides, Nucleotides & Nucleic Acids, 2000, 19, 827-838.

Matti R. Tarkka, Mikko Vuolle, Seppo Kaukinen, Päivi Holm, Jussi Eloranta, Ulla Kaukinen, Tero Sisto, Jukka Kataja
Effect of allopurinol on myocardial oxygen free radical production in coronary bypass surgery
Scandinavian Cardiovascular Journal, 2000, 34, 593-596.

Matti R. Tarkka, Seppo Kaukinen, Päivi Holm, Ulla Kaukinen, Tero Sisto, Jukka Kataja, Wen-Qi Huang
Allopurinol does not increase free radical scavenging capacity during reperfusion in coronary artery bypass graft patients
Scandinavian Cardiovascular Journal, 2000, 34, 409-414.

Riitta T. Aejmelaeus, Päivi Holm, Ulla Kaukinen, Timo J. A. Metsä-Ketelä, Pekka Laippala, Antti L. J. Hirvonen, Hannu E. R. Alho
Age-related changes in peroxyl radical scavenging capacity of human plasma
Free Radicals in Biology and Medicine, 1997, 23, 69-75.

Comments

Jeremy N. Harvey, Jolanta Zurek, Ulla Pentikäinen and Adrian J. Mulholland
Comment on ''Molecular dynamics DFT:B3LYP study of guanosinetriphosphate conversion into guanosinemonophosphate upon Mg2+ chelation of and phosphate oxygens of the triphosphate tail'' by Alexander A. Tulub, Phys. Chem. Chem. Phys., 2006, 8, 2187
Physical Chemistry Chemical Physics, 2006, 8, 5366-5367

Reviews

Satu Mikkola, Ulla Kaukinen, Harri Lönnberg
The effect of secondary structure on cleavage of the phosphodiester bonds of RNA
Cell Biochemistry and Biophysics, 2001, 34, 95-119