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Structure of human saposin A at lysosomal pH
Author(s) -
Hill Chris H.,
Read Randy J.,
Deane Janet E.
Publication year - 2015
Publication title -
acta crystallographica section f
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.572
H-Index - 37
ISSN - 2053-230X
DOI - 10.1107/s2053230x15008584
Subject(s) - hydrolase , chemistry , biochemistry , enzyme , galactocerebroside , stereochemistry , myelin , biology , neuroscience , oligodendrocyte , central nervous system
The saposins are essential cofactors for the normal lysosomal degradation of complex glycosphingolipids by acid hydrolase enzymes; defects in either saposin or hydrolase function lead to severe metabolic diseases. Saposin A (SapA) activates the enzyme β‐galactocerebrosidase (GALC), which catalyzes the breakdown of β‐D‐galactocerebroside, the principal lipid component of myelin. SapA is known to bind lipids and detergents in a pH‐dependent manner; this is accompanied by a striking transition from a `closed' to an `open' conformation. However, previous structures were determined at non‐lysosomal pH. This work describes a 1.8 Å resolution X‐ray crystal structure determined at the physiologically relevant lysosomal pH 4.8. In the absence of lipid or detergent at pH 4.8, SapA is observeed to adopt a conformation closely resembling the previously determined `closed' conformation, showing that pH alone is not sufficient for the transition to the `open' conformation. Structural alignments reveal small conformational changes, highlighting regions of flexibility.