Our Lab aims to gain molecular level understanding of fundamental biological processes, such as disease promoting host pathogen interactions, synthesis and remodeling of cell wall in multi-drug resistant bacteria, or contribution of protein structure, dynamics, and disorder to catalytic mechanisms of enzymes. Our research is highly interdisciplinary; combining methods in biophysics, biochemistry and microbiology that collectively offer superior means to decipher entangled scientific questions.
Overview
Core fields of research
Basic natural phenomena and mathematical thinking
Research areas
Nanobiology
Nanoscience Center
Health and well-being (NSC)
Functional Molecules and Materials
Chemical Nanoscience
Sustainable society
Faculty
Faculty of Mathematics and Science
Department
Department of Biological and Environmental Science
Department of Chemistry
Research group description
NMR spectroscopy stands as a unique technique amongst all biophysical tools enabling studies of biomolecular structures at atomic resolution in solution while simultaneously providing also site-specific data on dynamics and molecular interactions that regulate life at the molecular level. Our group seeks to understand protein function through characterization of structure, dynamics and interactions in solution. We mainly focus on proteins and molecular systems whose structures or interactions are dynamic and transient i.e. systems that are difficult to study with the X-ray crystallography e.g., intrinsically disordered proteins (IDPs) and modular systems.
We boost our efforts in structural and functional studies of biomolecules by participating strongly in NMR method development. We aim to advance and disseminate routines which help to obtain more information with reduced time and effort. Novel strategies devised for assignment of IDPs, as well as optimized methods developed for measuring structural and dynamical information on larger proteins, have had key role in studies of several challenging molecular targets.
Research expertise
Expertise of the research group spans from molecular (micro)biology and protein chemistry to structural biology/biophysics and molecular modelling, including various physical and chemical methods to study challenging biological questions. Our Lab has continuously aimed for improving our methodological ingenuity and employing latest innovations in NMR as well as other biophysical methods.
Characterization of structure, dynamics and interactions of various (bio)molecules in solution
Heterologous expression (E. coli & Baculovirus) and purification of proteins
Metabolomics using NMR spectroscopy
Development and application of NMR methodology
Research interests
Our current research is focused on:
Structural and functional characterization of peptidoglycan hydrolysing enzymes
Intrinsically disordered proteins/systems
Structural basis of pathogen-host interactions, especially bacterial and viral effectors targeting SH3 domains
Development of NMR methodology for structural and functional studies of biological molecules Keywords: EHEC/EPEC, IDPs, M23 peptidases, NMR spectroscopy, S. aureus, SH3 domains
Src homology 3 (SH3) domain is an abundant and perhaps the best-characterized structural unit found in modular signaling proteins. SH3 domains participate in a myriad of regulatory processes often involving formation of multimolecular complexes, where they typically bind proline-rich short linear motifs (SLIMs) found in several intrinsically disordered proteins or regions (IDPs/IDRs). The structural basis for recognition of classical SH3 binding ligands i.e. R/KxxPxxP or PxxPxR/K motifs (x= any amino acid) is well characterised. It has been recently shown that several SH3 domains bind with high affinity to ligand proteins which lack the conventional motifs. Indeed, in recent studies we and others have shown that the specificity and cellular functions of SH3s are far more diverse than earlier anticipated.
We have been studying several non-classical SH3 mediated interactions that involve cellular or bacterial IDPs/IDRs e.g., Eps8, CD3e, dynamin, EHEC EspFu, EHEC EspF, CHIKV nsP3, EEEV nsP3.
Our group has been mainly focused on applying biophysical techniques, especially NMR spectroscopy to address various biological questions. We also actively participate in the development of NMR methodology for structural and functional studies of biological molecules. We have focused on the measurement and usage various NMR parameters e.g., chemical shifts, scalar and residual dipolar couplings (RDCs) for structure determination and molecular interaction studies. We have had a major contribution to the development of NMR tools for the measurement and analysis of RDCs both in larger proteins and complexes as well as in intrinsically disordered proteins.
Antimicrobial resistance, the ability of microbes to defeat drugs designed to kill them, has rapidly spread globally, which has prompted WHO to forewarn of an impending, somber post-antibiotic world in which standard treatments become ineffective, simple infections unmanageable and fatal.
Peptidoglycan hydrolases (PGHs) represent a group of potential antibiotics against Gram-positive bacteria with a new bacteriocidic mechanism. Antibiotic action is based on hydrolysis of cell wall peptidoglycan (PG), which leads to cell lysis and death. Emergence of resistance against PGHs is expected to be low because of their narrow target spectrum and the constitutive and conserved nature of PG.
Our research focuses on Lysostaphin, LytU and LytM, PGHs that cleave pentaglycine bridges uniquely found in S. aureus PG. Their specificity and lytic potency makes them attractive targets of drug development for S. aureus infections. Using several biophysical techniques, NMR as our principal data source, we bring forth detailed, comparative, atomic-scale knowledge on enzyme–PG interactions, which dictate target affinity, specificity and enzymatic activity. Our multidisciplinary research paves the way to structure-level engineering to control specificity not only against different Staphylococci but also against other Gram-positive pathogens.
Enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic Escherichia coli (EHEC) bacteria are both pathogens that cause gastrointestinal disease. Both bacteria make harm to host organisms by translocating type III effector proteins to host cells through a protein translocation apparatus termed the type III secretion system. With the effector proteins these two bacteria hijack eukaryotic signalling pathways and cause attaching/effacing lesions to intestinal cells. The formation of attaching/effacing lesions is critical for the pathogenesis. How bacteria do this, is not yet fully understood. We are studying two different type III effector proteins: LEE-encoded effector EspF (EspF) and Secreted effector protein EspF(u) (EspFu) to gain more knowledge over this subject.
Both bacteria EPEC and EHEC have EspF protein, but EspFu protein can only be found from EHEC bacteria. Although EspFu is 25% identical (35% similar) at the amino acid level to EspF, it has a distinct biological function. This is an intriguing observation and reasoning it could reveal novel interactions in these two biological systems. In addition, both proteins EspF and EspFu, are intrinsically disordered proteins.
Publication list
For PhD students
No open PhD student positions open at the moment. Stay tuned for position openings in near future!
Postdocs
For post docs there are funding possibilities such as Marie Skłodowska-Curie Fellowships and various foundations. If you are interested in applying we are willing to help at all stages of application procedure.
Visitors
We very much welcome both short and long term visiting researchers or students to our Lab. Please send inquiry to Perttu Permi.
For students
M.Sc. and B.Sc. projects available, please contact Perttu Permi.
