scholarly journals Sterol transfer by atypical cholesterol-binding NPC2 proteins in coral-algal symbiosis

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Elizabeth Ann Hambleton ◽  
Victor Arnold Shivas Jones ◽  
Ira Maegele ◽  
David Kvaskoff ◽  
Timo Sachsenheimer ◽  
...  
Keyword(s):  
Low Ph ◽  
Algal Symbiosis ◽  
Cell Components ◽  
Niemann Pick ◽  
Cholesterol Binding

Reef-building corals depend on intracellular dinoflagellate symbionts that provide nutrients. Besides sugars, the transfer of sterols is essential for corals and other sterol-auxotrophic cnidarians. Sterols are important cell components, and variants of the conserved Niemann-Pick Type C2 (NPC2) sterol transporter are vastly up-regulated in symbiotic cnidarians. Types and proportions of transferred sterols and the mechanism of their transfer, however, remain unknown. Using different pairings of symbiont strains with lines of Aiptasia anemones or Acropora corals, we observe both symbiont- and host-driven patterns of sterol transfer, revealing plasticity of sterol use and functional substitution. We propose that sterol transfer is mediated by the symbiosis-specific, non-canonical NPC2 proteins, which gradually accumulate in the symbiosome. Our data suggest that non-canonical NPCs are adapted to the symbiosome environment, including low pH, and play an important role in allowing corals to dominate nutrient-poor shallow tropical seas worldwide.

scholarly journals Enhanced Stability of Non-Canonical NPC2 in the symbiosome supports coral-algal symbiosis

2018 ◽  
Author(s):  
Elizabeth A. Hambleton ◽  
Victor A.S. Jones ◽  
Ira Maegele ◽  
David K vaskoff ◽  
Timo Sachsenheimer ◽  
...  
Keyword(s):  
Low Ph ◽  
Nutrient Transfer ◽  
Cholesterol Trafficking ◽  
Pharmacological Inhibition ◽  
Algal Symbiosis ◽  
Specific Expansion ◽  
Niemann Pick ◽  
Enhanced Stability ◽  
Over Time ◽  
Sterol Trafficking

AbstractCnidarians such as reef-building corals depend upon nutrient transfer from intracellular symbionts, but the mechanisms and evolution of this process remain unknown. Homologues of the conserved cholesterol binder Niemann-Pick Type C2 (NPC2) in cnidarians are implicated in the transfer of sterol from symbionts. Here, we show that symbionts transfer bulk sterols to the host, host sterol utilization is plastic, and pharmacological inhibition of sterol trafficking disrupts symbiosis. Having undergone an anthozoan-specific expansion, “non-canonical” NPC2s respond to symbiosis and accumulate over time at the lysosomal-like organelle in which the symbiont resides (“symbiosome”). We demonstrate that both a non- and canonical Aiptasia NPC2 bind symbiont-produced sterols, yet only the non-canonical homologue exhibits increased stability at low pH. We propose that symbiotic cnidarians adapted pre-existing cholesterol-trafficking machinery to function in the highly acidic symbiosome environment, allowing corals to dominate nutrient-poor shallow tropical seas worldwide.

Lysosomal disease

2020 ◽  
pp. 2121-2156
Author(s):  
Patrick B. Deegan ◽  
Timothy M. Cox
Keyword(s):  
Single Gene ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Biological Macromolecules ◽  
Post Translational Modification ◽  
Lysosomal Disease ◽  
Lysosomal Diseases ◽  
Cell Components ◽  
Energy Sensing ◽  
Niemann Pick ◽  
The Individual

The lysosome is a ubiquitous, single membrane-bond intracellular organelle which continuously recycles biological macromolecules: it not only breaks down cell components but has a dynamic role in nutrient and energy sensing that, through regulatory signalling, is critical for homeostasis and metabolic economy of the cell. More than 80 lysosomal diseases caused by single gene defects are known. Biochemical classification identifies (1) sphingolipidoses; (2) mucopolysaccharidoses; (3) glycoproteinoses; (4) glycogenosis, with or without lysosomal debris derived from subcellular organelles due to impaired autophagy; and (5) miscellaneous conditions with multiple classes of storage material such as the neuronal ceroid lipofuscinoses. Functional classification describes deficiency of (1) a specific acid hydrolase activity, (2) an activator protein, (3) a lysosomal membrane protein or transporter, or (4) abnormal post-translational modification of lysosomal proteins, and (5) abnormal biogenesis of lysosomes. A unified classification will emerge from genetic characterization integrated with clinicopathological manifestations of the individual disorders. Fabry’s and Gaucher’s diseases (glycosphingolipidoses) are probably the most frequent in the general population, but certain lysosomal diseases are over-represented in particular groups where consanguinity or endogamy is high. Other diseases discussed in this chapter include (1) cystinosis, (2) the mucopolysaccharidoses, (3) Pompe’s disease (glycogen storage disease type II), (4) Niemann–Pick diseases, (5) lysosomal acid lipase deficiency, (6) Danon’s disease, and (7) diseases more recently attributed to primary defects in lysosomes and related organelles.

scholarly journals Simulations of NPC1(NTD):NPC2 Protein Complex Reveal Cholesterol Transfer Pathways

2018 ◽  
Vol 19 (9) ◽  
pp. 2623 ◽  
Author(s):  
Milan Hodošček ◽  
Nadia Elghobashi-Meinhardt
Keyword(s):  
Protein Complex ◽  
Structural Features ◽  
Binding Energies ◽  
Lysosomal Storage ◽  
Binding Pockets ◽  
Niemann Pick ◽  
Dynamics Simulations ◽  
Ligand Transfer ◽  
Binding Interfaces ◽  
Cholesterol Binding

The Niemann Pick type C (NPC) proteins, NPC1 and NPC2, are involved in the lysosomal storage disease, NPC disease. The formation of a NPC1–NPC2 protein–protein complex is believed to be necessary for the transfer of cholesterol and lipids out of the late endosomal (LE)/lysosomal (Lys) compartments. Mutations in either NPC1 or NPC2 can lead to an accumulation of cholesterol and lipids in the LE/Lys, the primary phenotype of the NPC disease. We investigated the NPC1(NTD)–NPC2 protein–protein complex computationally using two putative binding interfaces. A combination of molecular modeling and molecular dynamics simulations reveals atomic details that are responsible for interface stability. Cholesterol binding energies associated with each of the binding pockets for the two models are calculated. Analyses of the cholesterol binding in the two models support bidirectional ligand transfer when a particular interface is established. Based on the results, we propose that, depending on the location of the cholesterol ligand, a dynamical interface between the NPC2 and NPC1(NTD) proteins exists. Structural features of a particular interface can lower the energy barrier and stabilize the passage of the cholesterol substrate from NPC2 to NPC1(NTD).

scholarly journals Cholesterol binding to the sterol-sensing region of Niemann Pick C1 protein confines dynamics of its N-terminal domain

2020 ◽  
Vol 16 (10) ◽  
pp. e1007554
Author(s):  
Vikas Dubey ◽  
Behruz Bozorg ◽  
Daniel Wüstner ◽  
Himanshu Khandelia
Keyword(s):  
Terminal Domain ◽  
Niemann Pick ◽  
Cholesterol Binding

scholarly journals Author response: Sterol transfer by atypical cholesterol-binding NPC2 proteins in coral-algal symbiosis

2019 ◽  
Author(s):  
Elizabeth Ann Hambleton ◽  
Victor Arnold Shivas Jones ◽  
Ira Maegele ◽  
David Kvaskoff ◽  
Timo Sachsenheimer ◽  
...  
Keyword(s):  
Author Response ◽  
Algal Symbiosis ◽  
Cholesterol Binding

scholarly journals Cholesterol binding to the sterol-sensing region of Niemann Pick C1 protein confines dynamics of its N-terminal domain

2019 ◽  
Author(s):  
Vikas Dubey ◽  
Behruz Bozorg ◽  
Daniel Wüstner ◽  
Himanshu Khandelia
Keyword(s):  
Conformational Dynamics ◽  
Feedback Mechanism ◽  
Lysosomal Membrane ◽  
Protein Activity ◽  
Terminal Domain ◽  
Allosteric Effector ◽  
Lysosomal Accumulation ◽  
Regulate Protein ◽  
Niemann Pick ◽  
Cholesterol Binding

AbstractLysosomal accumulation of cholesterol is a hallmark of Niemann Pick type C (NPC) disease caused by mutations primarily in the lysosomal membrane protein NPC1. NPC1 contains a transmembrane sterol sensing domain (SSD), which is supposed to regulate protein activity upon cholesterol binding, but the mechanisms underlying this process are poorly understood. Using atomistic simulations, we show that the binding of cholesterol to the SSD of NPC1 suppresses conformational dynamics of the luminal domains which otherwise bring the luminal N-terminal domain (NTD) closer to the lipid bilayer. The presence of an additional 20% membrane cholesterol has negligible impact on this process. We propose that cholesterol acts as an allosteric effector, and the modulation of NTD dynamics by the SSD-bound cholesterol constitutes an allosteric feedback mechanism in NPC1 which controls cholesterol abundance in the lysosomal membrane.

scholarly journals Structure of a cholesterol-binding protein deficient in Niemann-Pick type C2 disease

2003 ◽  
Vol 100 (5) ◽  
pp. 2512-2517 ◽  
Author(s):  
N. Friedland ◽  
H.-L. Liou ◽  
P. Lobel ◽  
A. M. Stock
Keyword(s):  
Binding Protein ◽  
Niemann Pick ◽  
Cholesterol Binding

Ultrastructure of Giant Mitochondria and Their Inclusions in Schwann Cells of Bovine Splenic Nerve

1974 ◽  
Vol 32 ◽  
pp. 194-195
Author(s):  
Å. Thureson-Klein
Keyword(s):  
Schwann Cells ◽  
Cell Organelles ◽  
Giant Mitochondria ◽  
Matrix Density ◽  
Physiological Conditions ◽  
Unmyelinated Axons ◽  
Internal Structures ◽  
Structural Abnormalities ◽  
Cytotoxic Compounds ◽  
Cell Components

Giant mitochondria of various shapes and with different internal structures and matrix density have been observed in a great number of tissues including nerves. In most instances, the presence of giant mitochondria has been associated with a known disease or with abnormal physiological conditions such as anoxia or exposure to cytotoxic compounds. In these cases degenerative changes occurred in other cell organelles and, therefore the giant mitochondria also were believed to be induced structural abnormalities.Schwann cells ensheating unmyelinated axons of bovine splenic nerve regularly contain giant mitochondria in addition to the conventional smaller type (Fig. 1). These nerves come from healthy inspected animals presumed not to have been exposed to noxious agents. As there are no drastic changes in the small mitochondria and because other cell components also appear reasonably well preserved, it is believed that the giant mitochondria are normally present jin vivo and have not formed as a post-mortem artifact.

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