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J. Biol. Chem., Vol. 276, Issue 32, 29854-29863, August 10, 2001
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,
From the Department of Neuroscience, The Johns Hopkins University
School of Medicine, Baltimore, Maryland 21205
A key feature of the regulated secretory pathway
in neuroendocrine cells is lumenal pH, which decreases between
trans-Golgi network and mature secretory granules. Because
peptidylglycine 
-amidating monooxygenase (PAM) is one of the few
membrane-spanning proteins concentrated in secretory granules and is a
known effector of regulated secretion, we examined its sensitivity to
pH. Based on antibody binding experiments, the noncatalytic linker
regions between the two enzymatic domains of PAM show
pH-dependent conformational changes; these changes occur in
the presence or absence of a transmembrane domain. Integral membrane
PAM-1 solubilized from rat anterior pituitary or from transfected
AtT-20 cells aggregates reversibly at pH 5.5 while retaining enzyme
activity. Over 35% of the PAM-1 in anterior pituitary extracts
aggregates at pH 5.5, whereas only about 5% aggregates at pH 7.5. PAM-1 recovered from secretory granules and endosomes is highly
responsive to low pH-induced aggregation, whereas PAM-1 recovered from
a light, intracellular recycling compartment is not. Mutagenesis
studies indicate that a transmembrane domain is necessary but not
sufficient for low pH-induced aggregation and reveal a short lumenal,
juxtamembrane segment that also contributes to pH-dependent
aggregation. Taken together, these results demonstrate that several
properties of membrane PAM serve as indicators of granule pH in
neuroendocrine cells.
Present address: Center for Experimental Therapeutics, University
of Pennsylvania School of Medicine, Philadelphia, PA 19104.
§
Present address: Dept. of Neuroscience, University of Connecticut
Health Center, 263 Farmington Ave., Farmington, CT 06030-3401.
¶
To whom correspondence should be addressed: Dept. of
Neuroscience, MC3401, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030-3401. Tel.: 860-679-8894;
Fax: 860-679-1060; E-mail: mains@uchc.edu.
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