Investigation of ANXA11 Membrane Anchoring Mechanisms and the Impacts of Mutations Associated with Amyotrophic Lateral Sclerosis

• Grant number: 24/10159-1
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: January 01, 2025
• End date: December 31, 2029
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Luis Felipe Santos Mendes
• Grantee: Rodrigo Jose Silva Sena
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil

Abstract

Cellular integrity in mechanically active tissues depends on efficient membrane repair mechanisms. ANXA11, a protein from the annexin family with an unusually long and disordered N-terminal, is recruited to different membrane compartments in response to variations in intracellular calcium levels. Although its role in RNA granule transport via lysosomes and in plasma membrane repair has been suggested, the mechanisms governing these functions are still poorly understood and often based on contradictory information. This project aims to investigate the role of ANXA11 in membrane anchoring and its contribution to cellular repair. The focus will be on clarifying the factors that promote the preferential anchoring of ANXA11 to lysosomal membranes under physiological conditions and what triggers its relocation to the plasma membrane in response to the abrupt increase in intracellular calcium, characteristic of injury sites, as well as exploring the molecular mechanisms underlying these functions. The impact of the D40G and D40Y mutations, associated with Amyotrophic Lateral Sclerosis (ALS), will also be investigated, particularly in the formation of biomolecular condensates, potentially involved in repair pathways, and in the interaction with lysosomal membrane models.