TY - JOUR
T1 - Structural Basis of Molecular Recognition of the Leishmania Small Hydrophilic Endoplasmic Reticulum-associated Protein (SHERP) at Membrane Surfaces
AU - Moore, Benjamin
AU - Miles, Andrew J.
AU - Guerra-Giraldez, Cristina
AU - Simpson, Peter
AU - Iwata, Momi
AU - Wallace, B. A.
AU - Matthews, Stephen J.
AU - Smith, Deborah F.
AU - Brown, Katherine A.
PY - 2011/3/18
Y1 - 2011/3/18
N2 - The 57-residue small hydrophilic endoplasmic reticulum-associated protein (SHERP) shows highly specific, stage-regulated expression in the non-replicative vector-transmitted stages of the kinetoplastid parasite, Leishmania major, the causative agent of human cutaneous leishmaniasis. Previous studies have demonstrated that SHERP localizes as a peripheral membrane protein on the cytosolic face of the endoplasmic reticulum and on outer mitochondrial membranes, whereas its high copy number suggests a critical function in vivo. However, the absence of defined domains or identifiable orthologues, together with lack of a clear phenotype in transgenic parasites lacking SHERP, has limited functional understanding of this protein. Here, we use a combination of biophysical and biochemical methods to demonstrate that SHERP can be induced to adopt a globular fold in the presence of anionic lipids or SDS. Cross-linking and binding studies suggest that SHERP has the potential to form a complex with the vacuolar type H+-ATPase. Taken together, these results suggest that SHERP may function in modulating cellular processes related to membrane organization and/or acidification during vector transmission of infective Leishmania.
AB - The 57-residue small hydrophilic endoplasmic reticulum-associated protein (SHERP) shows highly specific, stage-regulated expression in the non-replicative vector-transmitted stages of the kinetoplastid parasite, Leishmania major, the causative agent of human cutaneous leishmaniasis. Previous studies have demonstrated that SHERP localizes as a peripheral membrane protein on the cytosolic face of the endoplasmic reticulum and on outer mitochondrial membranes, whereas its high copy number suggests a critical function in vivo. However, the absence of defined domains or identifiable orthologues, together with lack of a clear phenotype in transgenic parasites lacking SHERP, has limited functional understanding of this protein. Here, we use a combination of biophysical and biochemical methods to demonstrate that SHERP can be induced to adopt a globular fold in the presence of anionic lipids or SDS. Cross-linking and binding studies suggest that SHERP has the potential to form a complex with the vacuolar type H+-ATPase. Taken together, these results suggest that SHERP may function in modulating cellular processes related to membrane organization and/or acidification during vector transmission of infective Leishmania.
KW - Endoplasmic Reticulum
KW - Leishmania major
KW - Protein Folding
KW - Protein Structure, Tertiary
KW - Protozoan Proteins
KW - Vacuolar Proton-Translocating ATPases
UR - http://www.scopus.com/inward/record.url?scp=79953177469&partnerID=8YFLogxK
U2 - 10.1074/jbc.M110.130427
DO - 10.1074/jbc.M110.130427
M3 - Article
C2 - 21106528
SN - 0021-9258
VL - 286
SP - 9246
EP - 9256
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 11
ER -