Jk. Kim et al., EVIDENCE THAT THE HINGE REGION PLAYS A ROLE IN MAINTAINING SERUM LEVELS OF THE MURINE IGG1 MOLECULE, Molecular immunology, 32(7), 1995, pp. 467-475
The site of the murine IgG1 molecule that regulates catabolism has rec
ently been shown to encompass amino acids that are located at the CH2-
CH3 domain interface. The CH2 and CH3 domains are connected to each ot
her by a relatively flexible ''mini-hinge'' region, and flexibility in
this region could clearly affect the orientation of the domains with
respect to each other. The internal movement of the CH2 domain depends
on the absence/presence of the hinge disulphide. The increased mobili
ty of the CH2 domain relative to the CH3 domain in a hingeless IgG or
Fc fragment may result in a conformational change at the CH2-CH3 domai
n interface and alter the accessibility of the residues that are invol
ved in catabolism control. To investigate this possibility, four Fe fr
agments which differ in the presence/absence of hinge disulphides and
hinge sequences have been analysed in both in vivo pharmacokinetic stu
dies and in vitro by limited proteolysis with pepsin. The data show th
at the presence of hinge disulphide(s) in the Fc fragment results in a
longer intravascular half life but a higher susceptibility to pepsin
attack. This, taken together with the knowledge that pepsin cleaves cl
ose to the CH2-CH3 domain interface, suggests that the longer half lif
e of disulphide linked Fc fragments relative to unlinked fragments may
be due to conformational differences in this region of the IgG molecu
le, and these conformational changes may affect the accessibility of t
he catabolic site for binding to putative protective Fc receptors.