The role of the C-terminal region on the oligomeric state and enzymatic activity of Trypanosoma cruzi hypoxanthine phosphoribosyl transferase
Hypoxanthine phosphoribosyl transferase from Trypanosoma cruzi (TcHPRT) is a critical enzyme for the survival of the parasite. This work demonstrates that the full-length form in solution adopts a stable and enzymatically active tetrameric form, exhibiting large inter-subunit surfaces. Although this...
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todo:paper_15709639_v1864_n6_p655_Valsecchi2023-10-03T16:26:54Z The role of the C-terminal region on the oligomeric state and enzymatic activity of Trypanosoma cruzi hypoxanthine phosphoribosyl transferase Valsecchi, W.M. Cousido-Siah, A. Defelipe, L.A. Mitschler, A. Podjarny, A. Santos, J. Delfino, J.M. Bisphosphonates Disorder C-terminal region Enzymatic activity modulation Proteolysis Quaternary structure Reversible oligomerization Stability bisphosphonic acid derivative hypoxanthine phosphoribosyltransferase oligomer biopolymer hypoxanthine phosphoribosyltransferase Article carboxy terminal sequence circular dichroism enzyme activity enzyme conformation fluorescence spectroscopy hydrodynamics oligomerization priority journal protein degradation protein quaternary structure protein unfolding Trypanosoma cruzi X ray crystallography amino acid sequence chemistry enzymology metabolism molecular genetics ultraviolet spectrophotometry Amino Acid Sequence Biopolymers Circular Dichroism Hypoxanthine Phosphoribosyltransferase Molecular Sequence Data Proteolysis Spectrophotometry, Ultraviolet Trypanosoma cruzi Hypoxanthine phosphoribosyl transferase from Trypanosoma cruzi (TcHPRT) is a critical enzyme for the survival of the parasite. This work demonstrates that the full-length form in solution adopts a stable and enzymatically active tetrameric form, exhibiting large inter-subunit surfaces. Although this protein irreversibly aggregates during unfolding, oligomerization is reversible and can be modulated by low concentrations of urea. When the C-terminal region, which is predicted as a disordered stretch, is excised by proteolysis, TcHPRT adopts a dimeric state, suggesting that the C-terminal region acts as a main guide for the quaternary arrangement. These results are in agreement with X-ray crystallographic data presented in this work. On the other hand, the C-terminal region exhibits a modulatory role on the enzyme, as attested by the enhanced activity observed for the dimeric form. Bisphosphonates act as substrate-mimetics, uncovering long-range communications among the active sites. All in all, this work contributes to establish new ways applicable to the design of novel inhibitors that could eventually result in new drugs against parasitic diseases. © 2016 Elsevier B.V. All rights reserved. Fil:Defelipe, L.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Santos, J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_15709639_v1864_n6_p655_Valsecchi |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Bisphosphonates Disorder C-terminal region Enzymatic activity modulation Proteolysis Quaternary structure Reversible oligomerization Stability bisphosphonic acid derivative hypoxanthine phosphoribosyltransferase oligomer biopolymer hypoxanthine phosphoribosyltransferase Article carboxy terminal sequence circular dichroism enzyme activity enzyme conformation fluorescence spectroscopy hydrodynamics oligomerization priority journal protein degradation protein quaternary structure protein unfolding Trypanosoma cruzi X ray crystallography amino acid sequence chemistry enzymology metabolism molecular genetics ultraviolet spectrophotometry Amino Acid Sequence Biopolymers Circular Dichroism Hypoxanthine Phosphoribosyltransferase Molecular Sequence Data Proteolysis Spectrophotometry, Ultraviolet Trypanosoma cruzi |
| spellingShingle |
Bisphosphonates Disorder C-terminal region Enzymatic activity modulation Proteolysis Quaternary structure Reversible oligomerization Stability bisphosphonic acid derivative hypoxanthine phosphoribosyltransferase oligomer biopolymer hypoxanthine phosphoribosyltransferase Article carboxy terminal sequence circular dichroism enzyme activity enzyme conformation fluorescence spectroscopy hydrodynamics oligomerization priority journal protein degradation protein quaternary structure protein unfolding Trypanosoma cruzi X ray crystallography amino acid sequence chemistry enzymology metabolism molecular genetics ultraviolet spectrophotometry Amino Acid Sequence Biopolymers Circular Dichroism Hypoxanthine Phosphoribosyltransferase Molecular Sequence Data Proteolysis Spectrophotometry, Ultraviolet Trypanosoma cruzi Valsecchi, W.M. Cousido-Siah, A. Defelipe, L.A. Mitschler, A. Podjarny, A. Santos, J. Delfino, J.M. The role of the C-terminal region on the oligomeric state and enzymatic activity of Trypanosoma cruzi hypoxanthine phosphoribosyl transferase |
| topic_facet |
Bisphosphonates Disorder C-terminal region Enzymatic activity modulation Proteolysis Quaternary structure Reversible oligomerization Stability bisphosphonic acid derivative hypoxanthine phosphoribosyltransferase oligomer biopolymer hypoxanthine phosphoribosyltransferase Article carboxy terminal sequence circular dichroism enzyme activity enzyme conformation fluorescence spectroscopy hydrodynamics oligomerization priority journal protein degradation protein quaternary structure protein unfolding Trypanosoma cruzi X ray crystallography amino acid sequence chemistry enzymology metabolism molecular genetics ultraviolet spectrophotometry Amino Acid Sequence Biopolymers Circular Dichroism Hypoxanthine Phosphoribosyltransferase Molecular Sequence Data Proteolysis Spectrophotometry, Ultraviolet Trypanosoma cruzi |
| description |
Hypoxanthine phosphoribosyl transferase from Trypanosoma cruzi (TcHPRT) is a critical enzyme for the survival of the parasite. This work demonstrates that the full-length form in solution adopts a stable and enzymatically active tetrameric form, exhibiting large inter-subunit surfaces. Although this protein irreversibly aggregates during unfolding, oligomerization is reversible and can be modulated by low concentrations of urea. When the C-terminal region, which is predicted as a disordered stretch, is excised by proteolysis, TcHPRT adopts a dimeric state, suggesting that the C-terminal region acts as a main guide for the quaternary arrangement. These results are in agreement with X-ray crystallographic data presented in this work. On the other hand, the C-terminal region exhibits a modulatory role on the enzyme, as attested by the enhanced activity observed for the dimeric form. Bisphosphonates act as substrate-mimetics, uncovering long-range communications among the active sites. All in all, this work contributes to establish new ways applicable to the design of novel inhibitors that could eventually result in new drugs against parasitic diseases. © 2016 Elsevier B.V. All rights reserved. |
| format |
JOUR |
| author |
Valsecchi, W.M. Cousido-Siah, A. Defelipe, L.A. Mitschler, A. Podjarny, A. Santos, J. Delfino, J.M. |
| author_facet |
Valsecchi, W.M. Cousido-Siah, A. Defelipe, L.A. Mitschler, A. Podjarny, A. Santos, J. Delfino, J.M. |
| author_sort |
Valsecchi, W.M. |
| title |
The role of the C-terminal region on the oligomeric state and enzymatic activity of Trypanosoma cruzi hypoxanthine phosphoribosyl transferase |
| title_short |
The role of the C-terminal region on the oligomeric state and enzymatic activity of Trypanosoma cruzi hypoxanthine phosphoribosyl transferase |
| title_full |
The role of the C-terminal region on the oligomeric state and enzymatic activity of Trypanosoma cruzi hypoxanthine phosphoribosyl transferase |
| title_fullStr |
The role of the C-terminal region on the oligomeric state and enzymatic activity of Trypanosoma cruzi hypoxanthine phosphoribosyl transferase |
| title_full_unstemmed |
The role of the C-terminal region on the oligomeric state and enzymatic activity of Trypanosoma cruzi hypoxanthine phosphoribosyl transferase |
| title_sort |
role of the c-terminal region on the oligomeric state and enzymatic activity of trypanosoma cruzi hypoxanthine phosphoribosyl transferase |
| url |
http://hdl.handle.net/20.500.12110/paper_15709639_v1864_n6_p655_Valsecchi |
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