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Evidence that the hinge region plays a role in maintaining serum levels of the murine IgG1 molecule

Evidence that the hinge region plays a role in maintaining serum levels of the murine IgG1 molecule
Evidence that the hinge region plays a role in maintaining serum levels of the murine IgG1 molecule

The site of the murine IgG1 molecule that regulates catabolism has recently been shown to encompass amino acids that are located at the CH2CH3 domain interface. The CH2 and CH3 domains are connected to each other 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 mobility of the CH2 domain relative to the CH3 domain in a hingeless IgG or Fc fragment may result in a conformational change at the CH2CH3 domain interface and alter the accessibility of the residues that are involved in catabolism control. To investigate this possibility, four Fc fragments which differ in the presence/absence of hinge disulphides and hinge sequences have been analysed in both in vivo pharmacokinetic studies and in vitro by limited proteolysis with pepsin. The data show that 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 close to the CH2CH3 domain interface, suggests that the longer half life of disulphide linked Fc fragments relative to unlinked fragments may be due to conformational differences in this region of the IgG molecule, and these conformational changes may affect the accessibility of the catabolic site for binding to putative protective Fc receptors.

conformational change, hinge region, IgG catabolism, limited proteolysis, recombinant Fc fragment
0161-5890
467-475
Kim, Jin Kyoo
3f679975-b86c-4b96-9571-499c2ad80378
Tsen, May Fang
ee928224-ae90-4cf6-8a0a-263e7f8ec057
Ghetie, Victor
b7b50946-2bd9-4896-b841-6bbfba8237c2
Sally Ward, E.
b31c0877-8abe-485f-b800-244a9d3cd6cc
Kim, Jin Kyoo
3f679975-b86c-4b96-9571-499c2ad80378
Tsen, May Fang
ee928224-ae90-4cf6-8a0a-263e7f8ec057
Ghetie, Victor
b7b50946-2bd9-4896-b841-6bbfba8237c2
Sally Ward, E.
b31c0877-8abe-485f-b800-244a9d3cd6cc

Kim, Jin Kyoo, Tsen, May Fang, Ghetie, Victor and Sally Ward, E. (1995) Evidence that the hinge region plays a role in maintaining serum levels of the murine IgG1 molecule. Molecular Immunology, 32 (7), 467-475. (doi:10.1016/0161-5890(95)00019-B).

Record type: Article

Abstract

The site of the murine IgG1 molecule that regulates catabolism has recently been shown to encompass amino acids that are located at the CH2CH3 domain interface. The CH2 and CH3 domains are connected to each other 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 mobility of the CH2 domain relative to the CH3 domain in a hingeless IgG or Fc fragment may result in a conformational change at the CH2CH3 domain interface and alter the accessibility of the residues that are involved in catabolism control. To investigate this possibility, four Fc fragments which differ in the presence/absence of hinge disulphides and hinge sequences have been analysed in both in vivo pharmacokinetic studies and in vitro by limited proteolysis with pepsin. The data show that 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 close to the CH2CH3 domain interface, suggests that the longer half life of disulphide linked Fc fragments relative to unlinked fragments may be due to conformational differences in this region of the IgG molecule, and these conformational changes may affect the accessibility of the catabolic site for binding to putative protective Fc receptors.

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More information

Accepted/In Press date: 6 January 1995
Published date: May 1995
Keywords: conformational change, hinge region, IgG catabolism, limited proteolysis, recombinant Fc fragment

Identifiers

Local EPrints ID: 425268
URI: https://eprints.soton.ac.uk/id/eprint/425268
ISSN: 0161-5890
PURE UUID: 2940e2dc-969c-46f4-b2ef-d8ed61e614a1
ORCID for E. Sally Ward: ORCID iD orcid.org/0000-0003-3232-7238

Catalogue record

Date deposited: 12 Oct 2018 16:30
Last modified: 22 May 2019 00:21

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Contributors

Author: Jin Kyoo Kim
Author: May Fang Tsen
Author: Victor Ghetie
Author: E. Sally Ward ORCID iD

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