Mariusz Jaskólski

Degrees

• 1985 - D.Sc. - physical chemistry and crystallography, UAM
• 1979 - Ph.D. - chemistry, UAM
• 1976 - M.Sc. - chemistry, UAM

Previous posts

• Visiting Scientist, Macromol. Struct. Lab., NCI-FCRDC (USA)

Honors

• International Research Scholar of the Howard Hughes Medical Institute (1994-2002)
• Corresponding Member of the Polish Academy of Sciences (elected 2002)
• Foundation for Polish Science Award (2002)
• Zawidzki Medal, awarded by the Polish Chemical Society (2003)
• Faculty Scholar, NCI (appointed 2004)
• Member of the European Molecular Biology Organization (elected 2004)
• Foreign Member, The Royal Society of Sciences at Uppsala (elected 2005)
• Parnas Award, awarded by the Polish Biochemical Society (2006)
• Marchlewski Medal, awarded by the Committee of Biochemistry and Biophysics, Polish Academy of Sciences (2009)

Postal address

Current research interests and achievements

My main field of expertise is crystallography. I have applied the techniques of crystal structure determination to study the following problems of structural chemistry and structural biology.

• Retroviral protease. In collaboration with Dr. Alex Wlodawer (NCI-FCRDC), the structure of the first retroviral protease (from Avian sarcoma virus) and of the (chemically synthesized) protease from HIV-1 have been determined showing that these enzymes belong to the class of aspartic proteases and establishing firm foundations for rational design of anti-AIDS drugs targeted at the maturation process of the HIV virus. Also, a complex of HIV-1 protease inactivated by a substrate-based inhibitor has been analyzed and a new view on the catalytic mechanism of retroviral proteases has been proposed. The first crystal structure of monomeric subunit of a retroviral protease (from Mason-Pfizer monkey virus, M-PMV) has been determined using a model built by players of the on-line game Foldit.

• Retroviral integrase. The crystal structure determined (together with Dr. Alex Wlodawer, NCI-FCRDC, and Dr. Anne Skalka, FCCC) for the catalytic domain of Avian sarcoma virus integrase revealed, for the first time, the complete and ordered active site of the enzyme as well as the location and possible role of the divalent cations which are required cofactors for the integration reaction.

• Bacterial asparaginases. The first structure of a bacterial asparaginase, from E. coli (a drug used in cancer therapy), has been determined leading to the identification of the active site, forming grounds for structure-based discussions of the catalytic mechanism, and providing a reliable model for further asparaginase/glutaminase structures. Current studies focus on mutants of bacterial asparaginases and on eukaryotic enzymes.

• Ntn hydrolases. A plant asparaginase (LlA) has been sequenced, cloned, expressed and crystallized. Its close analog (EcAIII) has been found in the E. coli genome. The structures of these proteins reveal that they are Ntn hydrolase. It has been found that in addition to their predicted asparaginase activity, they have more potent isoaspartyl aminopeptidase activities, but are inactive towards glycosylasparagine despite high sequence similarity to aspartylglucosaminidases. The crystal structure of an active-site mutant of EcAIII suggests a mechanism for the autocatalytic activation reaction.

• Pathogenesis-related proteins. The crystal structures of several homologs from the multi-gene family of plant pathogenesis-related proteins of class 10, reveal their similarity to common pollen allergens and suggest how they could bind small-molecule ligands. Among the studied proteins are those known to bind cytokinins, the plant hormones. The structure of a representative of these proteins has been determined in complex with the plant hormone zeatin at atomic resolution, revealing a puzzling dual mode of ligand binding.

• Cysteine proteases. Proteases in this family play a role in degenerative diseases, such as osteoporosis or muscular dystrophy. In our search of new compounds that could be used as drugs, we have determined the crystal structure of several complexs between the cysteine protease papain and different inhibitors (irreversible and peptidic) designed after the natural inhibitors, E-64 and human cystatin C. In addition, we determined the structure of the cysteine-protease inhibitor chagasin from Trypanosoma cruzi, the pathogenic protozoan that causes Chagas disease, both in its enzyme-free form and in complex with human cathepsins L and B, and with papain.

• Amyloidogenic proteins. Amyloid-forming proteins attract attention because of their role in the pathogenesis of several "conformational" diseases, like Alzheimer's disease and the prionoses. Human cystatin C, a potent and abundant protease inhibitor, is known to undergo pathological dimerization, and at advanced age forms amyloid deposits in the brain arteries. This tendency to aggregate is drastically amplified in the endemically occurring L68Q mutant. We have solved the crystal structure of human cystatin C in its dimeric form and demonstrated that the protein aggregates through exchange of structural units, in a process known as 3D domain swapping. The hinge allowing the protein to partially unfold and to refold in higher oligomeric state is part of the enzyme-binding epitope, which makes the dimer physiologically inactive as inhibitor of papain-class enzymes. The protein undergoes 3D domain swapping both in its full-length form and as an N-truncated peptide, which is the main product extracted from in vivo amyloid fibrils. In one of the crystal forms, the dimeric protein undergoes further aggregation via intermolecular beta sheets reminiscent of the cross-beta structure believed to exist in amyloid fibrils. Specific mutagenesis directed towards creating new disulfide bridges that would prevent domain swapping inhibits the dimerization process completely and greatly reduces the protein's ability to form amyloid fibrils in vitro. Dimerization can also be supressed by binding of exogenous agents, such as carboxymethylpapain or a monoclonal antibody.

• Structural chemistry of nucleic acids constituents. The structure of a number of nucleosides and their salts have been determined leading to a better understanding of the behavior of protonated vs. neutral nucleosides. The structures of phosphate salts of nucleosides revealed their structural preferences and opened new avenues for crystal engineering of nucleic acids constituents.

• Hydrogen bonding in solids. Several systems with very short O...O, N...O and N...N hydrogen bridges have been studied, including the so-called proton-sponges, also in deuterated form and in extremely low temperatures. Correlations of the parameters describing the D-H...A system have been discussed and a limit for the D-H...A angle has been proposed. In addition to extremely strong hydrogen bonds, C-H...A bonds and other non-classical interactions are also studied.

• Teaching. I have taught crystallography for many years. Recent courses focus on macromolecular crystallography. A textbook "Krystalografia dla biologow" ("Crystallography for Biologists") is a summary of my lecture course taught to biology students (in Polish). Lectures on Protein crystallization in iPod and mp3 format (English version) (wersja polska), crystallographic quiz, and "Crystallographic ABC" are freely available.

Lists available for viewing

• Selected publications
• Outside collaborators

Current research support

• Ministry of Education and Science grant for Structural and biochemical studies of plant PR-10 proteins from different sources
• Ministry of Education and Science grant for Structural aspects of nodulation proteins
• International PhD Programme Structural biology of plants and microbes, Foundation for Polish Science (coordinator)