4.6 Review

Review Structural advances in sterol-sensing domain-containing proteins

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Article Multidisciplinary Sciences

A structure of human Scap bound to Insig-2 suggests how their interaction is regulated by sterols

Renhong Yan et al.

Summary: The sterol regulatory element-binding protein (SREBP) pathway is controlled by membrane-embedded sterol sensors Scap, Insig-1 and Insig-2, with 25-hydroxycholesterol (25HC) serving as a master switch. Cryo-electron microscopy analysis revealed the structure of the human Scap and Insig-2 complex in the presence of 25HC, showing the critical role of 25HC binding and Insig association in regulating the pathway.

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Dispatched uses Na+ flux to power release of lipid-modified Hedgehog

Qianqian Wang et al.

Summary: The Dispatched protein is involved in tissue-patterning activity by releasing the lipid-modified Hedgehog protein. The protein's function is dependent on the Na+ gradient and the coordinated Na+ ions within its channel. Variants with disrupted Na+ binding show impaired export of the Hedgehog protein.

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Structural insights into proteolytic activation of the human Dispatched1 transporter for Hedgehog morphogen release

Wanqiu Li et al.

Summary: Dispatched (Disp) RND transporter, activated by Furin-mediated proteolytic cleavage, mediates the release of the lipid-modified Hedgehog (Hh) ligands. Structures of human Disp1 (hDisp1) before and after cleavage, and in complex with lipid-modified Sonic hedgehog (Shh), provide insights into the mechanisms of hDisp1 activation and function.

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Scap structures highlight key role for rotation of intertwined luminal loops in cholesterol sensing

Daniel L. Kober et al.

Summary: Cholesterol-sensing protein Scap regulates the transport of sterol regulatory element-binding proteins (SREBPs) from the endoplasmic reticulum to the Golgi apparatus, with cholesterol inhibiting Scap transport by binding to L1 and subsequently binding to Insig to inhibit cholesterol synthesis.
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Cristina Barale et al.

Summary: PCSK9 plays a key role in lipoprotein metabolism and atherosclerosis, with potential cardiovascular benefits from its inhibition. Currently, anti-PCSK9 antibodies and small interfering RNA are effective therapies to reduce LDL-C levels and attenuate cardiovascular disease.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Highly accurate protein structure prediction for the human proteome

Kathryn Tunyasuvunakool et al.

Summary: Using the AlphaFold method, the structural coverage of the proteome has been significantly expanded, covering 98.5% of human proteins with 58% of residues having confident predictions and 36% having very high confidence. Introducing new metrics to interpret the dataset and identify disordered regions, this study aims to provide high-quality predictions for generating biological hypotheses.

NATURE (2021)

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Cryo-EM study of patched in lipid nanodisc suggests a structural basis for its clustering in caveolae

Yitian Luo et al.

Summary: The study reconstituted Patched (Ptc1) into lipid nanodiscs and found that Ptc1 can form dimers under different membrane curvatures, providing a plausible framework for Ptc1 clustering in highly curved caveolae.

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Structural basis for sterol sensing by Scap and Insig

Renhong Yan et al.

Summary: Through a combination of cryogenic electron microscopy analysis and artificial intelligence-facilitated structural prediction, this study reveals the structure of the human Scap/Insig-2 complex. The luminal domains of Scap show similarities to those of NPC1 and related proteins, providing insights into the cholesterol-regulated interaction of specific loops. The study also demonstrates that a mutant Scap protein inhibits the SREBP pathway even under sterol depletion, suggesting its involvement in a later step in protein trafficking.

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Femke M. Feringa et al.

Summary: The brain tightly regulates cholesterol levels for physiological function, but excessive accumulation may contribute to Alzheimer's disease. Genetic risk factors associated with cholesterol metabolism may impact AD pathology. Advances in CRISPR/Cas9 gene editing and iPSC technology hold promise for further understanding these mechanisms.

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Structural insights into the mechanism of human NPC1L1-mediated cholesterol uptake

Miaoqing Hu et al.

Summary: NPC1L1 protein is crucial in intestinal cholesterol absorption, and ezetimibe can inhibit NPC1L1 to reduce cholesterol uptake. Cryo-electron microscopy structures revealed that SSD in NPC1L1 responds to alterations in cholesterol levels by binding different numbers of cholesterol molecules, with ezetimibe binding causing inhibition of NPC1L1 function through deformation of the SSD.

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Article Multidisciplinary Sciences

Structures of dimeric human NPC1L1 provide insight into mechanisms for cholesterol absorption

Tao Long et al.

Summary: NPC1L1 plays a crucial role in the absorption of dietary cholesterol, VE, and VK in the intestine. The study revealed that hNPC1L1 functions primarily as a homodimer, with mutations disrupting dimerization leading to reduced efficiency of cholesterol uptake. Targeting the oligomeric state of hNPC1L1 could be a potential therapeutic strategy for inhibiting cholesterol absorption and reducing the risk of cardiovascular disease.

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Hedgehog pathway activation through nanobody-mediated conformational blockade of the Patched sterol conduit

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The morphogen Sonic hedgehog inhibits its receptor Patched by a pincer grasp mechanism

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Michael S. Brown et al.

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Triazoles inhibit cholesterol export from lysosomes by binding to NPC1

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Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis

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Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2

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Binding between the Niemann-Pick C1 protein and a photoactivatable cholesterol analog requires a functional sterol-sensing domain

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Patched acts catalytically to suppress the activity of Smoothened

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The sterol-sensing domain: multiple families, a unique role?

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