Elucidating the impact of functional protein liquid and solid condensates in the secretory pathway

• Grant number: 22/06006-0
• Support Opportunities: Generation Project Research Grant
• Start date: August 01, 2023
• End date: July 31, 2028
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Luis Felipe Santos Mendes
• Grantee: Luis Felipe Santos Mendes
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Associated researchers: Antonio José da Costa Filho ; Eduardo Festozo Vicente ; Juliana Sakamoto Yoneda ; Mariana Raquel Bunoro Batista ; Vitor Hugo Balasco Serrão
• Associated scholarship(s): 24/10392-8 - Characterization of the Formation of Functional Solid Condensates of the Neuropeptides CRH and Neuropeptide Y in the Context of Anxiety and Depression, BP.DD; 23/12516-3 - Impact of N-terminal Acetylation on the structure and molecular interactions of the "GRASP65 homolog protein 1" from Saccharomyces cerevisiae, BP.MS; 23/13459-3 - Physicochemical analysis of the potential for liquid condensation via liquid-liquid phase separation in the Golgin family of proteins, BP.MS

Abstract

30% of all proteins encoded in humans are sorted and transported through the Endoplasmic Reticulum and Golgi complex. Despite the fluid interchange of components within these organelles, their structures remain stable and elastic. Thus, how these compartments are built and spatially organised to polarise the direction of protein secretion remains obscure. Furthermore, the molecular mechanisms determining how some secretory cargos can be packed, stored, and released are still not understood. The formation of biomolecular condensates and functional amyloids have recently emerged as novel strategies adopted by cells to organize their internal space. The condensation of intracellular biomolecules into "solid"-like and "liquid"-like phases has distinct implications beyond its dysregulation in neurodegenerative disorders. Protein self-association plays many roles in vivo, such as forming the liquid-like phases in membraneless organelles and biomolecular condensates (including the nucleolus and P-granules) and the amyloid-like formation of biofilms/hyphae. However, the study of functional condensates is still in its infancy and, therefore, requires further investigation. In this project, we propose to investigate the (un)structural biology of protein/peptide self-association to test the impact of "liquid" and "solid" protein condensates in two parallel hypotheses associated with the secretory pathway. The first assumes that liquid crystal-like phases formed by Golgi-matrix proteins could organise membrane compartments. Therefore, the Golgi would be essentially a "liquid" with a phase-separated internal organisation. The second hypothesis assumes that a natural step in storing and releasing of stress-associated neuropeptides in secretory granules would involve functional amyloids' dynamic assembly/disassembly without the need of a specialised cell machinery. Consequently, their aggregation in secretory granules and further release to the extracellular space are dependent solely on the different physical chemistry properties experienced along the secretory pathway. Our results will potentially impact and reshape one of the most well-studied cell biology processes (classical eukaryote exocytic pathway) and expand our knowledge of the overall relevance of protein condensates. (AU)

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)

MENDES, LUIS FELIPE S.; OLIVEIRA, CAROLINA G.; SIMOES, KEVIN F.; KAVA, EMANUEL; COSTA-FILHO, ANTONIO J.. Exploring liquid-liquid phase separation in the organisation of Golgi matrix proteins. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, v. 1872, n. 5, p. 10-pg., 2024-06-27. (22/06006-0, 21/10465-7)

MENDES, LUIS FELIPE S.; GIMENES, CAROLINA O.; DA SILVA, MARILIA D. O.; ROUT, SAROJ K.; RIEK, ROLAND; COSTA-FILHO, ANTONIO J.. The potential role of liquid-liquid phase separation in the cellular fate of the compartments for unconventional protein secretion. Protein Science, v. 33, n. 7, p. 16-pg., 2024-07-01. (22/06006-0, 15/50366-7, 09/54044-3, 21/10465-7, 20/15542-7)