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An antibody that prevents serpin polymerisation acts by inducing a novel allosteric behaviour.

Motamedi-Shad, N; Jagger, AM; Liedtke, M; Faull, SV; Nanda, AS; Salvadori, E; Wort, JL; ... Lomas, DA; + view all (2016) An antibody that prevents serpin polymerisation acts by inducing a novel allosteric behaviour. Biochemical Journal , 473 (19) pp. 3269-3290. 10.1042/BCJ20160159. Green open access

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Abstract

Serpins are important regulators of proteolytic pathways with an anti-protease activity that involves a conformational transition from a metastable to a hyperstable state. Certain mutations permit the transition to occur in the absence of a protease; when associated with an inter-molecular interaction, this yields linear polymers of hyperstable serpin molecules, which accumulate at the site of synthesis. This is the basis of a number of pathologies termed the serpinopathies. We have previously identified a monoclonal antibody (mAb4B12) that, in single-chain form, blocks α1-antitrypsin (α1-AT) polymerisation in cells. Here we describe the structural basis for this activity. The mAb4B12 epitope was found to encompass residues Glu32, Glu39, and His43 on helix A and Leu306 on helix I. This is not a region typically associated with the serpin mechanism of conformational change, and correspondingly the epitope was present in all tested structural forms of the protein. Antibody binding rendered β-sheet A - on the opposite face of the molecule - more liable to adopt an 'open' state, mediated by changes distal to the breach region and proximal to helix F. The allosteric propagation of induced changes through the molecule was evidenced by an increased rate of peptide incorporation and destabilisation of pre-formed serpin-enzyme complex following mAb4B12 binding. These data suggest that prematurely shifting the β-sheet A equilibrium towards the 'open' state out of sequence with other changes suppresses polymer formation. This work identifies a region potentially exploitable for rational design of ligands that is able to dynamically influence α1-AT polymerisation.

Type: Article
Title: An antibody that prevents serpin polymerisation acts by inducing a novel allosteric behaviour.
Open access status: An open access version is available from UCL Discovery
DOI: 10.1042/BCJ20160159
Publisher version: http://dx.doi.org/10.1042/BCJ20160159
Language: English
Additional information: © 2016 The Author(s) This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).
Keywords: allosteric regulation, antibodies, protein aggregation, protein conformation, protein-protein interactions, serpin
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > London Centre for Nanotechnology
UCL > Provost and Vice Provost Offices > VP Health
URI: http://discovery.ucl.ac.uk/id/eprint/1504732
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