Structure of human saposin A at lysosomal pH.

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Hill, Chris H 
Read, Randy J 
Deane, Janet E 

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.

GALC, lipid-transfer protein, saposin A, sphingolipid activator protein, Amino Acid Sequence, Crystallization, Crystallography, X-Ray, Humans, Hydrogen-Ion Concentration, Lysosomes, Molecular Sequence Data, Protein Structure, Secondary, Protein Structure, Tertiary, Saposins
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Acta Crystallogr F Struct Biol Commun
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International Union of Crystallography (IUCr)
Wellcome Trust (082961/Z/07/Z)
Royal Society (1562)
Wellcome Trust (100140/Z/12/Z)
CHH is funded by a Wellcome Trust PhD studentship, RJR is supported by a Principal Research Fellowship funded by the Wellcome Trust (Grant No. 082961/Z/07/Z) and JED is supported by a Royal Society University Research Fellowship (UF100371). The Cambridge Institute for Medical Research is supported by a Wellcome Trust Strategic Award (100140).