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J. Biol. Chem., Vol. 276, Issue 20, 16911-16918, May 18, 2001
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From the Centre for Immunology, Saint Vincent's Hospital and
University of New South Wales, Victoria Street, Sydney,
New South Wales 2010, Australia
Macrophage inhibitory cytokine-1 (MIC-1) is a
divergent member of the transforming growth factor-
The Propeptide of the Transforming Growth Factor-
Superfamily
Member, Macrophage Inhibitory Cytokine-1 (MIC-1), Is a Multifunctional
Domain That Can Facilitate Protein Folding and Secretion*
(TGF-)
superfamily. While it is synthesized in a pre-pro form, it is unique
among superfamily members because it does not require its propeptide
for correct folding or secretion of the mature peptide. To investigate
factors that enable these propeptide independent events to occur, we
constructed MIC-1/TGF-1 chimeras, both with and without a
propeptide. All chimeras without a propeptide secreted less efficiently
compared with the corresponding constructs with propeptide. Folding and secretion were most affected after replacement of the predicted major
-helix in the mature protein, residues 56-68. Exchanging the human
propeptide in this chimera with either the murine MIC-1 or TGF-1
propeptide resulted in secretion of the unprocessed, monomeric chimera,
suggesting a specific interaction between the human MIC-1 propeptide
and mature peptide. Propeptide deletion mutants enabled identification
of a region between residues 56 and 78, which is important for the
interaction between the propeptide and the mature peptide.
Cotransfection experiments demonstrated that the propeptide must be in
cis with the mature peptide for this phenomenon to occur.
These results suggest a model for TGF- superfamily protein folding.
*
This work was funded in part by grants from St.
Vincent's Hospital and by Meriton Apartments Proprietary Ltd.
through a research and development syndicate arranged by Macquarie Bank
Ltd., and by a New South Wales health research and development
infrastructure grant.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.:
61-2-8382-2590; Fax: 61-2-8382-2830; E-mail:
s.breit@cfi.unsw.edu.au.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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