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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.

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.