C-type lectin-(like) fold - Protein-protein interaction patterns and utilization

Abstract

The C-type lectin-like fold (CTL fold) is a building block of many proteins, including saccharide-binding lectins, natural killer cell receptors, macrophage mannose receptor, selectins, collectins, snake venoms and others. Some are important players in innate immunity and are involved in the first-line response to virally infected cells or cancer cells, some play a role in antimicrobial defense, and some are potential targets for fight against problems connected with allergies, obesity, and autoimmunity. The structure of a CTL domain typically contains two α-helices, two small β-sheets and a long surface loop, with two or three disulfide bridges stabilizing the structure. This small domain is often involved in interactions with a target molecule, however, utilizing varied parts of the domain surface, with or without structural modifications. More than 500 three-dimensional structures of CTL fold-containing proteins are available in the Protein Data Bank, including a significant number of complexes with their key interacting partners (protein:protein complexes). The amount of available structural data enables a detailed analysis of the rules of interaction patterns utilized in activation, inhibition, attachment, and other pathways or functionalities. Interpretation of known CTL receptor structures and all other CTL-containing proteins and complexes with described three-dimensional structures, complemented with sequence/structure/interaction correlation analysis, offers a comprehensive view of the rules of interaction patterns of the CTL fold. The results are of value for prediction of interaction behavior of so far not understood CTL-containing proteins and development of new protein binders based on this fold, with applications in biomedicine or biotechnologies. It follows from the available structural data that almost the whole surface of the CTL fold is utilized in protein:protein interactions, with the heaviest frequency of utilization in the canonical interaction region. The individual categories of interactions differ in the interface buildup strategy. The strongest CTL binders rely on interfaces with large interaction area, presence of hydrophobic core, or high surface complementarity. The typical interaction surfaces of the fold are not conserved in amino acid sequence and can be utilized in design of new binders for biotechnological applications.

Keywords: C-type lectin; C-type lectin-like; Immune system; MHC; NK receptor; Pathogen; Protein binder; Protein engineering; Protein-protein interaction; Snake venom.