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J Biol Chem, Vol. 275, Issue 2, 1300-1306, January 14, 2000
From the Cell Biology and Metabolism Branch and the
Hermansky-Pudlak syndrome (HPS) comprises a group
of genetic disorders characterized by defective lysosome-related
organelles. The most common form of HPS (HPS type 1) is caused by
mutations in a gene encoding a protein with no homology to any other
known protein. Here we report the identification and biochemical
characterization of this gene product, termed HPS1p. Endogenous HPS1p
was detected in a wide variety of human cell lines and exhibited an
electrophoretic mobility corresponding to a protein of ~80 kDa. In
contrast to previous theoretical analysis predicting that HPS1p is an
integral membrane protein, we found that this protein was predominantly cytosolic, with a small amount being peripherally associated with membranes. The sedimentation coefficient of the soluble form of HPS1p
was ~6 S as inferred from ultracentrifugation on sucrose gradients.
HPS1p-deficient cells derived from patients with HPS type 1 displayed
normal distribution and trafficking of the lysosomal membrane proteins,
CD63 and Lamp-1. This was in contrast to cells from HPS type 2 patients, having mutations in the
Molecular Characterization of the Protein Encoded by the
Hermansky-Pudlak Syndrome Type 1 Gene*
,, and Heritable Disorders Branch, NICHD, National Institutes of
Health, Bethesda, Maryland 20892
3A subunit of the AP-3 adaptor
complex, which exhibited increased routing of these lysosomal proteins
through the plasma membrane. Similar analyses performed on fibroblasts
from 10 different mouse models of HPS revealed that only the AP-3
mutants pearl and mocha display increased
trafficking of Lamp-1 through the plasma membrane. Taken together,
these observations suggest that the product of the HPS1 gene is a cytosolic protein capable of associating with membranes and
involved in the biogenesis and/or function of lysosome-related organelles by a mechanism distinct from that dependent on the AP-3 complex.
*
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.
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