How does membrane composition modulate cholesterol carrier protein NPC2?

Giray Enkavi, Heikki Mikkolainen, Burçin Güngör, Elina Maria Ikonen, Ilpo Tapio Vattulainen

Forskningsoutput: KonferensbidragPosterForskning

Sammanfattning

Niemann-Pick Protein C2 (NPC2) is a small soluble protein, which facilitates the endosomal/lysosomal cholesterol efflux, a vital step in cholesterol metabolism. Mutations in NPC2 causes Niemann-Pick C disease, in which lipid accumulation causes neuronal degeneration and early death. Specific lipids found in the lysosome/late endosome affect the efficiency of NPC2-mediated cholesterol transport, but the molecular mechanism of this activity modulation remains elusive. We performed atomistic molecular dynamics simulations and free energy calculations to investigate the effect of relevant lipids on NPC2-membrane binding. We characterize a mechanism for membrane association and two distinct membrane binding modes of NPC2: a “cholesterol-exchange mode” and an “idle mode”. We systematically show that i) anionic lipids are necessary and sufficient for unspecific membrane association; ii) a unique anionic lysosomal/endosomal lipid, BMP, however, is required for the “cholesterol exchange mode”; and iii) sphingomyelin (SM) counteracts BMP by favoring the “idle mode”. Our findings suggest that BMP and SM modulates NPC2-mediated cholesterol transport by favoring one of the two binding modes.
Originalspråkengelska
StatusPublicerad - 16 jul 2017
Evenemangthe 19th IUPAB Congress and 11th EBSA congress - Edinburgh International Conference Center, Edinburgh, Storbritannien
Varaktighet: 16 jul 201720 jul 2017
http://www.iupab2017.org/

Konferens

Konferensthe 19th IUPAB Congress and 11th EBSA congress
Förkortad titelIUPAB and EBSA 2017
LandStorbritannien
OrtEdinburgh
Period16/07/201720/07/2017
Internetadress

Citera det här

Enkavi, G., Mikkolainen, H., Güngör, B., Ikonen, E. M., & Vattulainen, I. T. (2017). How does membrane composition modulate cholesterol carrier protein NPC2?. Poster presenterad vid the 19th IUPAB Congress and 11th EBSA congress, Edinburgh, Storbritannien.
Enkavi, Giray ; Mikkolainen, Heikki ; Güngör, Burçin ; Ikonen, Elina Maria ; Vattulainen, Ilpo Tapio. / How does membrane composition modulate cholesterol carrier protein NPC2?. Poster presenterad vid the 19th IUPAB Congress and 11th EBSA congress, Edinburgh, Storbritannien.
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title = "How does membrane composition modulate cholesterol carrier protein NPC2?",
abstract = "Niemann-Pick Protein C2 (NPC2) is a small soluble protein, which facilitates the endosomal/lysosomal cholesterol efflux, a vital step in cholesterol metabolism. Mutations in NPC2 causes Niemann-Pick C disease, in which lipid accumulation causes neuronal degeneration and early death. Specific lipids found in the lysosome/late endosome affect the efficiency of NPC2-mediated cholesterol transport, but the molecular mechanism of this activity modulation remains elusive. We performed atomistic molecular dynamics simulations and free energy calculations to investigate the effect of relevant lipids on NPC2-membrane binding. We characterize a mechanism for membrane association and two distinct membrane binding modes of NPC2: a “cholesterol-exchange mode” and an “idle mode”. We systematically show that i) anionic lipids are necessary and sufficient for unspecific membrane association; ii) a unique anionic lysosomal/endosomal lipid, BMP, however, is required for the “cholesterol exchange mode”; and iii) sphingomyelin (SM) counteracts BMP by favoring the “idle mode”. Our findings suggest that BMP and SM modulates NPC2-mediated cholesterol transport by favoring one of the two binding modes.",
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Enkavi, G, Mikkolainen, H, Güngör, B, Ikonen, EM & Vattulainen, IT 2017, 'How does membrane composition modulate cholesterol carrier protein NPC2?' the 19th IUPAB Congress and 11th EBSA congress, Edinburgh, Storbritannien, 16/07/2017 - 20/07/2017, .

How does membrane composition modulate cholesterol carrier protein NPC2? / Enkavi, Giray; Mikkolainen, Heikki; Güngör, Burçin; Ikonen, Elina Maria; Vattulainen, Ilpo Tapio.

2017. Poster presenterad vid the 19th IUPAB Congress and 11th EBSA congress, Edinburgh, Storbritannien.

Forskningsoutput: KonferensbidragPosterForskning

TY - CONF

T1 - How does membrane composition modulate cholesterol carrier protein NPC2?

AU - Enkavi, Giray

AU - Mikkolainen, Heikki

AU - Güngör, Burçin

AU - Ikonen, Elina Maria

AU - Vattulainen, Ilpo Tapio

PY - 2017/7/16

Y1 - 2017/7/16

N2 - Niemann-Pick Protein C2 (NPC2) is a small soluble protein, which facilitates the endosomal/lysosomal cholesterol efflux, a vital step in cholesterol metabolism. Mutations in NPC2 causes Niemann-Pick C disease, in which lipid accumulation causes neuronal degeneration and early death. Specific lipids found in the lysosome/late endosome affect the efficiency of NPC2-mediated cholesterol transport, but the molecular mechanism of this activity modulation remains elusive. We performed atomistic molecular dynamics simulations and free energy calculations to investigate the effect of relevant lipids on NPC2-membrane binding. We characterize a mechanism for membrane association and two distinct membrane binding modes of NPC2: a “cholesterol-exchange mode” and an “idle mode”. We systematically show that i) anionic lipids are necessary and sufficient for unspecific membrane association; ii) a unique anionic lysosomal/endosomal lipid, BMP, however, is required for the “cholesterol exchange mode”; and iii) sphingomyelin (SM) counteracts BMP by favoring the “idle mode”. Our findings suggest that BMP and SM modulates NPC2-mediated cholesterol transport by favoring one of the two binding modes.

AB - Niemann-Pick Protein C2 (NPC2) is a small soluble protein, which facilitates the endosomal/lysosomal cholesterol efflux, a vital step in cholesterol metabolism. Mutations in NPC2 causes Niemann-Pick C disease, in which lipid accumulation causes neuronal degeneration and early death. Specific lipids found in the lysosome/late endosome affect the efficiency of NPC2-mediated cholesterol transport, but the molecular mechanism of this activity modulation remains elusive. We performed atomistic molecular dynamics simulations and free energy calculations to investigate the effect of relevant lipids on NPC2-membrane binding. We characterize a mechanism for membrane association and two distinct membrane binding modes of NPC2: a “cholesterol-exchange mode” and an “idle mode”. We systematically show that i) anionic lipids are necessary and sufficient for unspecific membrane association; ii) a unique anionic lysosomal/endosomal lipid, BMP, however, is required for the “cholesterol exchange mode”; and iii) sphingomyelin (SM) counteracts BMP by favoring the “idle mode”. Our findings suggest that BMP and SM modulates NPC2-mediated cholesterol transport by favoring one of the two binding modes.

M3 - Poster

ER -

Enkavi G, Mikkolainen H, Güngör B, Ikonen EM, Vattulainen IT. How does membrane composition modulate cholesterol carrier protein NPC2?. 2017. Poster presenterad vid the 19th IUPAB Congress and 11th EBSA congress, Edinburgh, Storbritannien.