Abstract
Interactions between proteins and glycans are critical to various biological processes. With databases of carbohydrate-interacting proteins and increasing amounts of structural data, the three-sided right-handed β-helix (RHBH) has emerged as a significant structural fold for glycan interactions. In this review, we provide an overview of the sequence, mechanistic, and structural features that enable the RHBH to interact with glycans. The RHBH is a prevalent fold that exists in eukaryotes, prokaryotes, and viruses associated with adhesin and carbohydrate-active enzyme (CAZyme) functions. An evolutionary trajectory analysis on structurally characterized RHBH-containing proteins shows that they likely evolved from carbohydrate-binding proteins with their carbohydrate-degrading activities evolving later. By examining three polysaccharide lyase and three glycoside hydrolase structures, we provide a detailed view of the modes of glycan binding in RHBH proteins. The 3-dimensional shape of the RHBH creates an electrostatically and spatially favorable glycan binding surface that allows for extensive hydrogen bonding interactions, leading to favorable and stable glycan binding. The RHBH is observed to be an adaptable domain capable of being modified with loop insertions and charge inversions to accommodate heterogeneous and flexible glycans and diverse reaction mechanisms. Understanding this prevalent protein fold can advance our knowledge of glycan binding in biological systems and help guide the efficient design and utilization of RHBH-containing proteins in glycobiology research.