Chemical and structural analysis of an antibody folding intermediate trapped during glycan biosynthesis

J Am Chem Soc. 2012 Oct 24;134(42):17554-63. doi: 10.1021/ja306068g. Epub 2012 Oct 15.

Abstract

Human IgG Fc glycosylation modulates immunological effector functions such as antibody-dependent cellular cytotoxicity and phagocytosis. Engineering of Fc glycans therefore enables fine-tuning of the therapeutic properties of monoclonal antibodies. The N-linked glycans of Fc are typically complex-type, forming a network of noncovalent interactions along the protein surface of the Cγ2 domain. Here, we manipulate the mammalian glycan-processing pathway to trap IgG1 Fc at sequential stages of maturation, from oligomannose- to hybrid- to complex-type glycans, and show that the Fc is structurally stabilized following the transition of glycans from their hybrid- to complex-type state. X-ray crystallographic analysis of this hybrid-type intermediate reveals that N-linked glycans undergo conformational changes upon maturation, including a flip within the trimannosyl core. Our crystal structure of this intermediate reveals a molecular basis for antibody biogenesis and provides a template for the structure-guided engineering of the protein-glycan interface of therapeutic antibodies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Humans
  • Immunoglobulin Fc Fragments / chemistry*
  • Immunoglobulin Fc Fragments / genetics
  • Models, Molecular
  • Molecular Structure
  • Polysaccharides / biosynthesis*
  • Polysaccharides / chemistry
  • Protein Folding

Substances

  • Immunoglobulin Fc Fragments
  • Polysaccharides