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Crystallographic studies of septins, their individual domains and their complexes

Grant number: 21/08158-9
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): September 01, 2021
Effective date (End): August 31, 2024
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal Investigator:Richard Charles Garratt
Grantee:Diego Antonio Leonardo Cabrejos
Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Associated research grant:20/02897-1 - Septin filaments: structure, polymerization and role in pathologies, AP.TEM


The main role of the postdoctoral fellow will be to consolidate the leading position in septin crystallography that the group proposing the thematic project currently occupies. There are still questions concerning the structure/function relationship of septins that need clarification and where the determination of new crystallographic structures has much to contribute. Considering the existence of both hexameric and octameric human septin oligomers, there are six different types of septin-septin interface that can exist when such oligomers associate to form filaments. As a result of our group's efforts over the past five years, four of these interfaces are now known at high resolution. Part of this proposal, therefore, will address the two missing interfaces so that we can reconstruct a complete picture of the filament with atomic details (a "divide and conquer" approach). Thus, this work will be complementary to another postdoctoral project that will focus on studies of the complete heterocomplex using cryo-electron microscopy. The interfaces of interest are formed between members of the SEPT6 and SEPT7 group and the homodimer formed by SEPT2. To stabilize the first interface an already planned mutant will be employed. For the case of the SEPT2-SEPT2 interface, we will use new constructions including the alpha-0 helix in order to obtain crystals that diffract higher resolution compared to those already reported in the literature. In addition, the Fellow will continue with efforts to crystallize other combinations of septins to broaden our knowledge of the details of specific selectivity between pairs of septins. For example, the first high-resolution structures of a dimeric heterocomplex resolved by our group allowed us to hypothesize a possible covalent bond between subunits involving the side chains of a cysteine (SEPT2) and a lysine (SEPT6). However, these residues are not always conserved in all group members. The consequences of this sequential variation in terms of preferences for the formation of specific pairs deserve to be investigated. Finally, the postdoctoral fellow will be responsible for continuing our attempts to crystallize a complete hexameric (or octameric) complex. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SILVA, RAFAEL MARQUES DA; SALADINO, GIOVANNA CHRISTE DOS REIS; LEONARDO, DIEGO ANTONIO; PEREIRA, HUMBERTO D'MUNIZ; ARAUJO, ANA PAULA ULIAN; GARRATT, RICHARD CHARLES. A key piece of the puzzle: The central tetramer of the Saccharomyces cerevisiae septin protofilament and its implications for self-assembly. Journal of Structural Biology, v. 215, n. 3, p. 13-pg., . (21/08158-9, 20/02897-1, 22/00125-7, 14/15546-1, 18/09687-2)
FERNANDES, ADRIANO DE FREITAS; LEONARDO, DIEGO ANTONIO; CAVINI, ITALO AUGUSTO; ROSA, HIGOR VINICIUS DIAS; VARGAS, JHON ANTONI; PEREIRA, HUMBERTO D'MUNIZ; NASCIMENTO, ALESSANDRO S.; GARRATT, RICHARD CHARLES. Conservation and divergence of the G-interfaces of Drosophila melanogaster septins. CYTOSKELETON, v. N/A, p. 16-pg., . (14/15546-1, 19/22000-9, 20/03983-9, 17/18173-0, 20/02897-1, 18/19992-7, 21/08158-9)

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