New Insights on the Sialidase Protein Family Revealed by a Phylogenetic Analysis in Metazoa

Abstract

Sialidases are glycohydrolytic enzymes present from virus to mammals that remove sialic acid from oligosaccharide chains. Four different sialidase forms are known in vertebrates: the lysosomal NEU1, the cytosolic NEU2 and the membrane-associated NEU3 and NEU4. These enzymes modulate the cell sialic acid content and are involved in several cellular processes and pathological conditions. Molecular defects in NEU1 are responsible for sialidosis, an inherited disease characterized by lysosomal storage disorder and neurodegeneration. The studies on the biology of sialic acids and sialyltransferases, the anabolic counterparts of sialidases, have revealed a complex picture with more than 50 sialic acid variants selectively present in the different branches of the tree of life. The gain/loss of specific sialoconjugates have been proposed as key events in the evolution of deuterostomes and Homo sapiens, as well as in the host-pathogen interactions. To date, less attention has been paid to the evolution of sialidases. Thus we have conducted a survey on the state of the sialidase family in metazoan. Using an in silico approach, we identified and characterized sialidase orthologs from 21 different organisms distributed among the evolutionary tree: Metazoa relative (Monosiga brevicollis), early Deuterostomia, precursor of Chordata and Vertebrata (teleost fishes, amphibians, reptiles, avians and early and recent mammals). We were able to reconstruct the evolution of the sialidase protein family from the ancestral sialidase NEU1 and identify a new form of the enzyme, NEU5, representing an intermediate step in the evolution leading to the modern NEU3, NEU4 and NEU2. Our study provides new insights on the mechanisms that shaped the substrate specificity and other peculiar properties of the modern mammalian sialidases. Moreover, we further confirm findings on the catalytic residues and identified enzyme loop portions that behave as rapidly diverging regions and may be involved in the evolution of specific properties of sialidases.

New Insights into Molecular Organization of Human Neuraminidase-1: Transmembrane Topology and Dimerization Ability

“…As underlined by Giacopuzzi et al 2,. NEU1 has several sequence specificities, notably in the region 316–333, which make it a unique enzyme in the sialidase family.…”

“…These enzymes are widely distributed and found in viruses, protozoa, bacteria, fungi, and vertebrates2. The human sialidase family contains four members: the lysosomal NEU1 (Swiss-Prot:Q99519), cytosolic NEU2, and membrane-bound NEU3 and NEU413.…”

Interface dynamics explain assembly dependency of influenza neuraminidase catalytic activity

“…Earlier work on metazoal non-iNAs reported the loop between the fourth and the fifth sheet of the propeller arrangement as region of iNA-specific insertion (Giacopuzzi, Bresciani, Schauer, Monti, & Borsani, 2012). This iNA-specific insertion includes a conserved binding site for a Ca 2+ ion (e.g.…”

NEU1 Sialidase Regulates the Sialylation State of CD31 and Disrupts CD31-driven Capillary-like Tube Formation in Human Lung Microvascular Endothelia

“…Although the numerous prokaryote and eukaryote members of the NEU superfamily share little amino acid (aa) sequence homology, they contain conserved motifs, including the Asp box (an aa sequence composed of SXDXGXTW) and the (F/Y)RIP motif (28). More recently, bioinformatic analysis has revealed high conservation of 6 residues essential for catalytic activity, including an Arg triad (Arg-21, Arg-237, and Arg-304), a Tyr/Glu nucleophile pair (Tyr-334 and Glu-218), and an Asp that functions as an acid/base catalyst (Asp-46) (31). Four putative phosphorylation sites at positions 384, 390, 569, and 865 were Ͼ90% conserved in all sialidases.…”