2026/01/08 by Emily Boyle, Sergio Cruz-León, Javier Lizarrondo +10 · 2 voices · 1 citation
Biochemistry, Genetics and Molecular Biology · Medicine · #Amorphous solid #Autophagy in Disease and Therapy #Cellular transport and secretion #High resolution #In situ #Macromolecule #Molecular dynamics #Phase (matter) #Point mutation #Protein Structure and Dynamics #Sequence (biology)
paper · doi:10.64898/2026.01.07.698105
published in bioRxiv (Cold Spring Harbor Laboratory) (Cold Spring Harbor Laboratory)
openalex publication_date 2026/01/08 · openalex created_date 2026/01/09 · openalex updated_date 2026/07/14
Abstract Biomolecular condensates organise cellular biochemistry, yet their molecular architecture in situ remains poorly understood. During selective autophagy, macromolecules frequently accumulate into biomolecular condensates, forming discrete entities for autophagic engulfment and degradation - ideal systems for structural analysis. We employed in situ cryo-electron tomography to determine the near-atomic resolution structure of Aminopeptidase 1 condensates within cells. These condensates form densely packed, spherical assemblies with amorphous organisation and liquid-like properties, elucidating the requirements of a selective autophagic cargo for exclusive targeting. Structural analysis and multiscale simulations reveal that the short, transient α-helical structures in the disordered N-terminus of Aminopeptidase 1 enable site-specific, coiled-coil-like interactions required for condensate formation and properties. A single point mutation that increases α-helical propensity directly modulates condensate viscosity and dynamics from a liquid-like to a glass-like state, while preserving local molecular packing. Our results demonstrate that disordered regions encode both specificity and material properties through transiently structured motifs, linking sequence specificity to phase behaviour in cells and expanding the molecular logic of phase separation in cells.