Global analysis of VHHs framework regions with a structural alphabet.
The VHHs are antigen-binding region/domain of camelid heavy chain antibodies (HCAb). They have many interesting biotechnological and biomedical properties due to their small size, high solubility and stability, and high affinity and specificity for their antigens. HCAb and classical IgGs are evolutionary related and share a common fold. VHHs are composed of regions considered as constant, called the frameworks (FRs) connected by Complementarity Determining Regions (CDRs), a highly variable region that provide interaction with the epitope. Actually, no systematic structural analyses had been performed on VHH structures despite a significant number of structures. This work is the first study to analyse the structural diversity of FRs of VHHs. Using a structural alphabet that allows approximating the local conformation, we show that each of the four FRs do not have a unique structure but exhibit many structural variant patterns. Moreover, no direct simple link between the local conformational change and amino acid composition can be detected. These results indicate that long-range interactions affect the local conformation of FRs and impact the building of structural models.
INSERM, U 1134, DSIMB, F-75739 Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, UMR_S 1134, F-75739 Paris, France; Institut National de la Transfusion Sanguine (INTS), F-75739 Paris, France; Laboratoire d'Excellence GR-Ex, F-75739 Paris, France.
Floriane
F
Noël
Atragene, F-94200 Ivry-sur-Seine, France.
Alain
A
Malpertuy
INSERM, U 1134, DSIMB, F-75739 Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, UMR_S 1134, F-75739 Paris, France; Institut National de la Transfusion Sanguine (INTS), F-75739 Paris, France; Laboratoire d'Excellence GR-Ex, F-75739 Paris, France. Electronic address: alexandre.debrevern@univ-paris-diderot.fr.
Alexandre G
AG
de Brevern
D000595:Amino Acid Sequence; D000818:Animals; D001666:Binding Sites, Antibody / Q000235:genetics / Q000276:immunology; D002161:Camelids, New World / Q000235:genetics / Q000276:immunology; D002162:Camelus / Q000235:genetics / Q000276:immunology; D022801:Complementarity Determining Regions / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D018360:Crystallography, X-Ray; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D008958:Models, Molecular; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity
D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region
Antibodies; Frameworks; Secondary structure; Sequence structure relationship; Structural alphabet