How does membrane composition modulate cholesterol carrier protein NPC2?

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

Research output: Conference materialsPosterResearch

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.
Original languageEnglish
Publication statusPublished - 16 Jul 2017
Eventthe 19th IUPAB Congress and 11th EBSA congress - Edinburgh International Conference Center, Edinburgh, United Kingdom
Duration: 16 Jul 201720 Jul 2017
http://www.iupab2017.org/

Conference

Conferencethe 19th IUPAB Congress and 11th EBSA congress
Abbreviated titleIUPAB and EBSA 2017
CountryUnited Kingdom
CityEdinburgh
Period16/07/201720/07/2017
Internet address

Cite this

Enkavi, G., Mikkolainen, H., Güngör, B., Ikonen, E. M., & Vattulainen, I. T. (2017). How does membrane composition modulate cholesterol carrier protein NPC2?. Poster session presented at the 19th IUPAB Congress and 11th EBSA congress, Edinburgh, United Kingdom.
Enkavi, Giray ; Mikkolainen, Heikki ; Güngör, Burçin ; Ikonen, Elina Maria ; Vattulainen, Ilpo Tapio. / How does membrane composition modulate cholesterol carrier protein NPC2?. Poster session presented at the 19th IUPAB Congress and 11th EBSA congress, Edinburgh, United Kingdom.
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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, United Kingdom, 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 session presented at the 19th IUPAB Congress and 11th EBSA congress, Edinburgh, United Kingdom.

Research output: Conference materialsPosterResearch

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 session presented at the 19th IUPAB Congress and 11th EBSA congress, Edinburgh, United Kingdom.