Immunoglobulin G1 Fc domain motions: implications for Fc engineering.

ABSTRACT: The fragment crystallizable (Fc) region links the key pathogen identification and destruction properties of immunoglobulin G (IgG). Pathogen opsonization positions Fcs to activate pro-inflammatory Fc? receptors (Fc?Rs) on immune cells. The cellular response and committal to a damaging, though protective, immune response are tightly controlled at multiple levels. Control mechanisms are diverse and in many cases unclear, but one frequently suggested contribution originates in Fc?R affinity being modulated through shifts in Fc conformational sampling. Here, we report a previously unseen IgG1 Fc conformation. This observation motivated an extensive molecular dynamics investigation of polypeptide and glycan motions that revealed greater amplitude of motion for the N-terminal C?2 domains and N-glycan than previously observed. Residues in the C?2/C?3 interface and disulfide-bonded hinge were identified as influencing the C?2 motion. Our results are consistent with a model of Fc that is structurally dynamic. Conformational states that are competent to bind immune-stimulating Fc?Rs interconverted with Fc conformations distinct from those observed in Fc?R complexes, which may represent a transient, nonbinding population.

SUBMITTER: Frank M 

PROVIDER: S-EPMC4041121 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature