Structure of human saposin A at lysosomal pH. Issue 7 (1st July 2015)

• Record Type: Journal Article
• Authors: Hill, Chris H.; Read, Randy J.; Deane, Janet E.
• Is Part Of: Acta crystallographica. Volume 71:Issue 7(2015:Jul.)
• Page Start: 895
• Page End: 900
• Publication Date: 2015-07-01
• Subjects: Crystallography -- Periodicals; Crystals -- Periodicals; 548
• DOI: 10.1107/S2053230X15008584
• Languages: English
• ISSNs: 2053-230X

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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.</p> </abstract>