Septin filaments: structure, polymerization and role in pathologies

• Grant number: 20/02897-1
• Support Opportunities: Research Projects - Thematic Grants
• Start date: May 01, 2021
• End date: April 30, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Richard Charles Garratt
• Grantee: Richard Charles Garratt
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Pesquisadores principais: Ana Paula Ulian de Araujo
• Associated researchers: Alessandro Silva Nascimento ; Humberto D'Muniz Pereira ; Italo Augusto Cavini ; Jörg Kobarg ; José Fernando Ruggiero Bachega ; Rodrigo Villares Portugal
• Associated research grant(s): 21/07927-9 - Multiuser Equipment approved in grant 2020/02897-1: liquid chromatography system AKTA Go, AP.EMU
• Associated scholarship(s): 24/20432-7 - Studies of septin complexes using electron microscopy and cryomicroscopy, BP.PD; 23/06866-1 - Application of transmission electron microscopy and single-particle analysis in the structural study of septin complexes., BP.TT; 22/02684-3 - Studies of septin complexes using electron microscopy and cryomicroscopy, BP.PD; + associated scholarships 22/00152-4 - Septins from Magnaporthe oryzae: a strctural approach, BP.DD; 22/00125-7 - The structural biology of septins in model organisms, BP.DD; 21/08158-9 - Crystallographic studies of septins, their individual domains and their complexes, BP.PD; 18/19992-7 - Structural studies of septin heteromeric coiled-coils by nuclear magnetic resonance spectroscopy, BP.PD - associated scholarships

Abstract

Septins are cytoskeletal GTP-binding proteins involved in key cellular events including cytokinesis, vesicle trafficking and exocytosis. In humans, different septins self associate in a specific manner to form hexameric or octameric heterocomplexes. These interact via their extremities to form filaments which are capable of assembling into higher order structures. It is known that ectopic expression, deletion and/or mutation of septin-coding genes is associated with a wide range of pathologies including infertility, neuropathies and several types of tumour. In the nervous system, for example, where septins are abundant and involved in almost all stages of neuronal development, abnormalities in the expression and function of septins has been associated with aging and neurodegenerative disorders. A complete understanding of the physiological roles of septins and the dysfunctions which lead to different pathologies with which they are associated, demands a wider knowledge of all aspects of the biochemical context where septins are important components. Amongst others, critical aspects include a better understanding of: their three-dimensional structure and its relationship with GTP binding and hydrolysis; the phenomenon of polymerization and membrane association; the organization of higher-order structures (bundles, networks etc.) andtheir protein binding partners. With a view to clarifying several of these physiological aspects of septin function, the applicants (who are responsible for the greater part of our current knowledge concerning the structures of septins and their filaments) propose the use of e series of complementary approaches, including the determination of further three-dimensional structures using X-ray diffraction and cryo-electron microscopy, complementary computational studies using simulation techniques and the identification of septin binding partners. Specific examples of the contributions we expect to make include understanding the mechanism associated with septin 2 cleavage by the NS3/2b protein from Zika virus, which is believed to be associated with neuropathy and the study of the association between septins and botulinum toxin light chains. (AU)

Scientific publications

(8)

(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)

CAVINI, ITALO A.; FONTES, MARINA G.; ZERAIK, ANA ELIZA; LOPES, JOSE L. S.; ARAUJO, ANA PAULA U.. Novel lipid-interaction motifs within the C-terminal domain of Septin10 from Schistosoma mansoni. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, v. 1866, n. 7, p. 9-pg., 2024-07-19. (18/19992-7, 16/13961-7, 22/01951-8, 20/02897-1)

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., 2023-06-16. (21/08158-9, 20/02897-1, 22/00125-7, 14/15546-1, 18/09687-2)

CASTRO, DANIELLE K. S. V.; ROSA, HIGOR V. D.; MENDONC, DEBORAH C.; CAVINI, ITALO A.; ARAUJO, ANA P. U.; GARRATT, RICHARD C.. Dissecting the Binding Interface of the Septin Polymerization Enhancer Borg BD3. Journal of Molecular Biology, v. 435, n. 13, p. 16-pg., 2023-05-10. (14/15546-1, 18/20209-5, 18/19992-7, 20/02897-1)

MENDONCA, D.; MORAIS, S.; PINTO, A.; LEONARDO, D.; VALADARES, N.; PORTUGAL, R.; KLAHOLZ, B.; GARRATT, R.; ARAUJO, A. P.. How to self assemble: oligomeric structures of septin complexes and sub-complexes from Ciona intestinalis. FEBS OPEN BIO, v. 14, p. 1-pg., 2024-06-01. (21/08158-9, 20/02897-1, 23/06866-1, 18/20209-5)

CAVINI, ITALO A.; WINTER, ASHLEY J.; PEREIRA, HUMBERTO D'MUNIZ; WOOLFSON, DEREK N.; CRUMP, MATTHEW P.; GARRATT, RICHARD C.. X-ray structure of the metastable SEPT14-SEPT7 coiled coil reveals a hendecad region crucial for heterodimerization. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, v. 79, p. 14-pg., 2023-10-01. (18/19992-7, 22/00262-4, 14/15546-1, 20/02897-1)

CAVINI, ITALO A.; LEONARDO, DIEGO A.; ROSA, HIGOR V. D.; CASTRO, DANIELLE K. S. V.; D'MUNIZ PEREIRA, HUMBERTO; VALADARES, NAPOLEAO F.; ARAUJO, ANA P. U.; GARRATT, RICHARD C.. The Structural Biology of Septins and Their Filaments: An Update. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 9, NOV 19 2021. (14/15546-1, 18/19992-7, 20/02897-1, 16/04658-9, 19/22000-9)

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., 2023-01-03. (14/15546-1, 19/22000-9, 20/03983-9, 17/18173-0, 20/02897-1, 18/19992-7, 21/08158-9)

MENDONCA, DEBORAH C.; MORAIS, SINARA T. B.; CIOL, HELOISA; PINTO, ANDRESSA P. A.; LEONARDO, DIEGO A.; PEREIRA, HUMBERTO D'MUNIZ; VALADARES, NAPOLEAO F.; V. PORTUGAL, RODRIGO; KLAHOLZ, BRUNO P.; GARRATT, RICHARD C.; et al. Structural Insights into Ciona intestinalis Septins: Complexes Suggest a Mechanism for Nucleotide-dependent Interfacial Cross-talk. Journal of Molecular Biology, v. 436, n. 16, p. 20-pg., 2024-07-10. (21/10247-0, 21/08158-9, 23/06866-1, 18/20209-5, 20/02897-1)