Annexin A11: Calcium-Dependent Regulation and Implications in Neurodegenerative Disease Pathogenesis

Annexins are calcium-dependent phospholipid-binding proteins that play critical roles in maintaining organismal health and cellular homeostasis. They are implicated in diverse biological processes, including anticoagulation, cell signaling, proliferation, apoptosis, vesicle trafficking, and membrane repair. Annexin A11 (AnxA11), a unique member of this family, possesses an unusually long and intrinsically disordered N-terminal domain, which is essential for its ability to form biomolecular condensates, and has been linked to various pathological conditions such as systemic autoimmune diseases and sarcoidosis. Notably, multiple ALS-associated mutations have been identified within this disordered region of the protein, highlighting its potential relevance in neurodegenerative disease. Despite increasing interest, the functional implications of AnxA11's interaction with calcium ions—particularly in modulating its disordered domain and condensate behavior—remain poorly understood. This project aims to elucidate the biophysical and structural consequences of calcium binding to AnxA11. We will investigate how calcium modulates the conformational landscape and dynamic behavior of the protein, as well as its propensity to form biomolecular condensates. Preliminary findings indicate that AnxA11 undergoes significant structural changes upon calcium binding. Moreover, calcium appears to enhance AnxA11’s capacity for condensate formation—an emergent property not typically observed in annexins involved in membrane repair under physiological conditions. This study will further explore how ALS-associated mutations affect calcium sensitivity, structural changes, and condensate dynamics, providing novel insights into the calcium-dependent regulation of AnxA11 and its potential role in ALS pathogenesis.

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP # 2024/10159-1) and by University of São Paulo.