| Full text | |
| Author(s): Show less - |
Scota Ferreira, Amanda Petrina
[1]
;
Cassago, Alexandre
[2]
;
Goncalves, Kaliandra de Almeida
[1]
;
Dias, Marilia Meira
[1]
;
Adamoski, Douglas
[1]
;
Rodrigues Ascencao, Carolline Fernanda
[1]
;
Honorato, Rodrigo Vargas
[1]
;
de Oliveira, Juliana Ferreira
[1]
;
Ferreira, Igor Monteze
[1]
;
Fornezari, Camila
[1]
;
Bettini, Jefferson
[2]
;
Lopes Oliveira, Paulo Sergio
[1]
;
Paes Leme, Adriana Franco
[1]
;
Portugal, Rodrigo Villares
[2]
;
Berteli Ambrosio, Andre Luis
[1]
;
Gomes Dias, Sandra Martha
[1]
Total Authors: 16
|
| Affiliation: | [1] CNPEM, Lab Nacionais Biociencias, BR-13083100 Campinas, SP - Brazil
[2] CNPEM, BR-13083100 Campinas, SP - Brazil
Total Affiliations: 2
|
| Document type: | Journal article |
| Source: | Journal of Biological Chemistry; v. 288, n. 39, p. 28009-28020, SEP 27 2013. |
| Web of Science Citations: | 28 |
| Abstract | |
The phosphate-dependent transition between enzymatically inert dimers into catalytically capable tetramers has long been the accepted mechanism for the glutaminase activation. Here, we demonstrate that activated glutaminase C(GAC) self-assembles into a helical, fiber-like double-stranded oligomer and propose a molecular model consisting of seven tetramer copies per turn per strand interacting via the N-terminal domains. The loop (LRFNKL326)-L-321 is projected as the major regulating element for self-assembly and enzyme activation. Furthermore, the previously identified in vivo lysine acetylation (Lys(311) in humans, Lys(316) in mouse) is here proposed as an important down-regulator of superoligomer assembly and protein activation. Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide, a known glutaminase inhibitor, completely disrupted the higher order oligomer, explaining its allosteric mechanism of inhibition via tetramer stabilization. A direct correlation between the tendency to self-assemble and the activity levels of the three mammalian glutaminase isozymes was established, with GAC being the most active enzyme while forming the longest structures. Lastly, the ectopic expression of a fiber-prone superactive GAC mutant in MDA-MB 231 cancer cells provided considerable proliferative advantages to transformed cells. These findings yield unique implications for the development of GAC-oriented therapeutics targeting tumor metabolism. (AU) | |
| FAPESP's process: | 12/14298-9 - Cancer metabolic adaptation: structural and functional studies of key proteins |
| Grantee: | Andre Luis Berteli Ambrosio |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 10/05003-0 - Structural and functional studies of key proteins underlying the metabolic adaptation process in tumors |
| Grantee: | Andre Luis Berteli Ambrosio |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 09/10875-9 - Cellular and biochemical studies of the glutaminase enzyme and its relation with cancer |
| Grantee: | Sandra Martha Gomes Dias |
| Support Opportunities: | Research Grants - Young Investigators Grants |
| FAPESP's process: | 10/05987-0 - Structural determination of the kidney type glutaminase and the search for its binding partners. |
| Grantee: | Alexandre Cassago |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |
| FAPESP's process: | 09/54067-3 - Acquisition of a mass spectrometer coupled to a liquid chromatography system for increasing the capacity to meet the needs of users and for making new technologies available in the Laboratory of Mass Spectrometry |
| Grantee: | Adriana Franco Paes Leme |
| Support Opportunities: | Multi-user Equipment Program |
| FAPESP's process: | 11/06654-7 - Screening of natural extracts for glycolytic and glutaminolytic inhibitory properties as a platform for searching new anti-tumours compounds |
| Grantee: | Kaliandra de Almeida Gonçalves |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |