Publikacje | Wydział Chemii

Publikacje 2016

Designing peptidic inhibitors of serum amyloid A aggregation process

Marta Sosnowska, Sandra Skibiszewska, Emilia Kamińska, Ewa Wieczerzak, Elżbieta Jankowska

Amino Acids, 2016, Vol. 48, iss. 4, pp. 1069-1078

Abstract:

Amyloid A amyloidosis is a life-threatening complication of a wide range of chronic inflammatory, infectious and neoplastic diseases, and the most common form of systemic amyloidosis worldwide. It is characterized by extracellular tissue deposition of fibrils that are composed of fragments of serum amyloid A protein (SAA), a major acute-phase reactant protein, produced predominantly by hepatocytes. Currently, there are no approved therapeutic agents directed against the formation of fibrillar SAA assemblies. We attempted to develop peptidic inhibitors based on their similarity and complementarity to the regions critical for SAA self-association, which they should interact with and block their assembly into amyloid fibrils. Inh1 and inh4 which are comprised of the residues from the amyloidogenic region of SAA1.1 protein and Aβ peptide, respectively, were found by us as capable to significantly suppress aggregation of the SAA1-12 peptide. It was chosen as an aggregation model that mimicks the amyloidogenic nucleus of SAA protein. We suppose that aromatic interactions may be responsible for inhibitory activity of both compounds. We also recognized that aromatic residues are involved in self-association of SAA1-12.

Read on-line: http://link.springer.com/article/10.1007%2Fs00726-015-2167-y

 

Epitope location for two monoclonal antibodies against human cystatin C, representing opposite aggregation inhibitory properties

Izabela Behrendt, Martyna Prądzińska, Marta Spodzieja, Aleksandra S. Kołodziejczyk, Sylwia Rodziewicz-Motowidło, Aneta Szymańska, Paulina Czaplewska

Amino Acids. - 2016, Vol. 48, iss. 7, s. 1717-1729

Abstract:

Human cystatin C (hCC), like many other amyloidogenic proteins, dimerizes and possibly makes aggregates by subdomain swapping. Inhibition of the process should suppress the fibrillogenesis leading to a specific amyloidosis (hereditary cystatin C amyloid angiopathy, HCCAA). It has been reported that exogenous agents like monoclonal antibodies against cystatin C are able to suppress formation of cystatin C dimers and presumably control the neurodegenerative disease. We have studied in detail two monoclonal antibodies (mAbs) representing very different aggregation inhibitory potency, Cyst10 and Cyst28, to find binding sites in hCC sequence responsible for the immunocomplex formation and pave the way for possible immunotherapy of HCCAA. We used the epitope extraction/excision mass spectrometry approach with the use of different enzymes complemented by affinity studies with synthetic hCC fragments as a basic technique for epitope identification. The results were analyzed in the context of hCC structure allowing us to discuss the binding sites for both antibodies. Epitopic sequences for clone Cyst28 which is a highly potent dimerization inhibitor were found in N-terminus, loop 1 and 2 (L1, L2) and fragments of β2 and β3 strands. The crucial difference between conformational epitope sequences found for both mAbs seems to be the lack of interactions with hCC via N-terminus and the loop 1 in the case of mAb Cyst10. Presumably the interactions of mAbs with hCC via L1 and β sheet fragments make the hCC structure rigid and unable to undergo the swapping process.

Read on-line: http://link.springer.com/article/10.1007%2Fs00726-016-2242-z

 

Isolation and characterization of autoantibodies against human cystatin C

Martyna Prądzińska, Izabela Behrendt, Marta Spodzieja, Aleksandra S. Kołodziejczyk, Sylwia Rodziewicz-Motowidło, Aneta Szymańska, Susanna L. Lundström, Roman A. Zubarev, Katarzyna Macur, Paulina Czaplewska

Amino Acids. - 2016, online first, Published June 8

Abstract:

Hereditary cystatin C amyloid angiopathy (HCCAA) is a severe neurodegenerative disorder related to the point mutation in cystatin C gene resulting in human cystatin C (hCC) L68Q variant. One of the potential immunotherapeutic approaches to HCCAA treatment is based on naturally occurring antibodies against cystatin C. A recent growing interest in autoantibodies, especially in the context of neurodegenerative diseases, emerges from their potential use as valuable diagnostic markers and for controlling protein aggregation. In this work, we present characteristics of natural anti-hCC antibodies isolated from the IgG fraction of human serum by affinity chromatography. The electrophoresis (1-D and 2-D) results demonstrated that the isolated NAbs are a polyclonal mixture, but their electrophoretic properties did not allow to classify the new autoantibodies to any particular type of IgG. The Fc-glycan status of the studied autoantibodies was assessed using mass spectrometry analysis. For the isolated NAbs, the epitopic fragments in hCC sequence were identified by MS-assisted proteolytic excision of the immune complex and compared with the ones predicted theoretically. The knowledge of hCC fragments binding to NAbs and other ligands may contribute to the search for new diagnostic methods for amyloidosis of different types and the search for their treatment.

Read on-line: http://link.springer.com/article/10.1007%2Fs00726-016-2271-7

 

Publikacje

Treść ostatnio zmodyfikowana przez: Aneta Szymańska
Treść wprowadzona przez: Aneta Szymańska
Ostatnia modyfikacja: 
wtorek, 19 lipca 2016 roku, 20:54