Dimerization of Human Angiogenin and of Variants Involved in Neurodegenerative Diseases

Human Angiogenin (hANG, or ANG, 14.1 kDa) promotes vessel formation and is also called RNase 5 because it included in the pancreatic-type ribonuclease (pt-RNase) super-family. Although low, its ribonucleolytic activity crucial for angiogenesis tumor tissues but physiological development of Central Nervous System (CNS) neuronal progenitors. Nevertheless, some ANG variants are involved both neurodegenerative Parkinson disease (PD) Amyotrophic Lateral Sclerosis (ALS). Notably, pt-RNases acquire new biological functions upon oligomerization. Considering diseases correlation with massive protein aggregation, we analyzed aggregation propensity three pathogenic variants, namely H13A, S28N, R121C. We found no wt-ANG, as well S28N R121C can form an enzymatically active dimer, which ANG-D. By contrast, inactive H13A-ANG does not dimerize. Corroborated by a specific cross-linking analysis behavior that turn lacks one two His site residues necessary to self-associate through three-dimensional domain swapping (3D-DS), demonstrate actually dimerizes 3D-DS. Then, deduce size exclusion chromatography (SEC) modeling ANG-D forms N-termini. In light these novelties, expect future investigations unveil other determinants possibly related onset and/or pathologies.