Biophysical characterization of insoluble aggregates of a multi-domain protein: an insight into the role of the various domains.

Abstract:

:Insoluble (visible) aggregates of a homodimer fusion glycoprotein, consisting of the first extracellular domain of a human protein, fused to the hinge, C(H)2, and C(H)3 domains of a human immunoglobulin G(1) (IgG(1)), were observed during early formulation development. The soluble fraction of the fusion protein was compared to the visible aggregates by various biophysical techniques such as intrinsic and ANS fluorescence emission, reducing and nonreducing SDS-PAGE, equilibrium folding and refolding experiments in urea and guanidine hydrochloride in the absence and presence of mercaptoethanol. Significant differences were observed between the visible aggregates and the supernatant. Partial unfolding of the aggregated molecules was detected by intrinsic and ANS fluorescence. Using urea and guanidine hydrochloride unfolding/solubilization and refolding curves, it was possible to extrapolate that (i) the aggregates were not covalently linked but tightly associated, (ii) the fused domains of the protein were unfolded but not involved in the aggregation process, (iii) the C(H)2 domains were native-like, and (iv) the C(H)3 domains were involved in the aggregation process.

journal_name

J Pharm Sci

authors

Souillac PO

doi

10.1002/jps.20423

subject

Has Abstract

pub_date

2005-09-01 00:00:00

pages

2069-83

issue

9

eissn

0022-3549

issn

1520-6017

pii

S0022-3549(16)31837-8

journal_volume

94

pub_type

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