Patched 1 regulates Smoothened by controlling sterol binding to its extracellular cysteine-rich domain

Kinnebrew, Maia; Woolley, Rachel E.; Ansell, T. Bertie; Byrne, Eamon F.X.; Frigui, Sara; Luchetti, Giovanni; Sircar, Ria; Nachtergaele, Sigrid; Mydock-McGrane, Laurel; Krishnan, Kathiresan; Newstead, Simon; Sansom, Mark S. P.; Covey, Douglas F.; Siebold, Christian; Rohatgi, Rajat

doi:10.1126/sciadv.abm5563

Cited by 29 publications

(34 citation statements)

References 78 publications

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“…It is intriguing how a simple lipid molecule like cholesterol can constitute a molecular target and subsequently bind to a protein motif located outside the plasma membrane. There is, however, a precedent of this molecular interaction: in the Smoothened (SMO) protein, a G protein-coupled receptor, cholesterol binds to the extracellular cysteine-rich domain, located outside the extracellular leaflet of the plasma membrane [40] . Fantini et al [41] , [42] described a ganglioside-binding domain in the NTD, which could enable the binding of SARS-CoV-2 to the plasma membrane-lipid Lo domains.…”

Section: Resultsmentioning

confidence: 99%

Role of cholesterol-recognition motifs in the infectivity of SARS-CoV-2 variants

Baier

Barrantes

2023

Colloids and Surfaces B: Biointerfaces

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Section: Resultsmentioning

confidence: 99%

Role of cholesterol-recognition motifs in the infectivity of SARS-CoV-2 variants

Baier

Barrantes

2023

Colloids and Surfaces B: Biointerfaces

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“…Strikingly, the same phenotypic reversal was achieved by the co-expression of the cholesterol pump Patched (Ptc) 41 that depletes the plasma membrane of cholesterol 4 . This suggests an indirect “second messenger” role of plasma membrane cholesterol not only in the regulation of Smoothened downstream of Ptc 41, 42, 43 , but also in the regulation of Shh shedding downstream of Disp (Fig. S2E) 4 .…”

Section: Resultsmentioning

confidence: 96%

Two-way Dispatched function in Sonic hedgehog shedding and transfer to high-density lipoproteins

Ehring

Ehlers

Froese

et al. 2023

Preprint

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The Sonic hedgehog (Shh) signaling pathway controls embryonic development and tissue homeostasis after birth. This requires regulated solubilization of dual-lipidated, firmly plasma membrane-associated Shh precursors from producing cells. Although it is firmly established that the resistance-nodulation-division transporter Dispatched (Disp) drives this process, it is less clear how lipidated Shh solubilization from the plasma membrane is achieved. We previously showed that Disp enhances proteolytic Shh solubilization from its lipidated terminal peptide anchors. This process, called shedding, converts tightly membrane-associated hydrophobic Shh precursors into delipidated soluble proteins. We show here that Disp-mediated Shh shedding is modulated by a serum factor that we identify as high-density lipoprotein (HDL). In addition to serving as soluble sinks for free membrane cholesterol, HDLs also accept the cholesterol-modified Shh peptide from Disp. The cholesteroylated Shh peptide is required and sufficient for Disp-mediated transfer because mCherry linked to cholesteroylated peptides associates with HDL in a Disp-dependent manner, but an N-palmitoylated Shh variant that lacks C-cholesterol does not. Disp-mediated Shh transfer to HDL is finalized by proteolytic processing of the palmitoylated N-terminal membrane anchor. The resulting mono-lipidated Shh variant may help meet the demands for Hh activity regulation in different cell types and developing tissues.

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“…SMO is a member of the GPCR family of receptors, one of the most studied classes of membrane receptors involved in signal transduction across the plasma membrane ( Katritch et al, 2013 ; Chattopadhyay, 2014 ; Sakmar, 2017 ). Although the role of cholesterol in mediating a varied aspects of GPCR function such as signaling, stability, oligomerization, endocytosis and trafficking constitutes an exciting contemporary area of research ( Pucadyil and Chattopadhyay, 2006 ; Paila and Chattopadhyay, 2010 ; Oates and Watts, 2011 ; Goddard and Watts, 2012 ; Chattopadhyay, 2014 ; Sengupta and Chattopadhyay, 2015 ; Gimpl, 2016 ; Sengupta et al, 2018 ; Jafurulla et al, 2019 ; Kiriakidi et al, 2019 ; Sarkar et al, 2020 ; Jakubík and El-Fakahany, 2021 ; Kumar and Chattopadhyay, 2021a ; Sarkar et al, 2022 ; Sarkar and Chattopadhyay, 2022 ), activation of SMO by cholesterol has recently added a new functional dimension to this area of work ( Luchetti et al, 2016 ; Kinnebrew et al, 2022 ; Kumari et al, 2022 ).…”

Section: Defective Hedgehog Signaling In Slosmentioning

confidence: 99%

Smith-Lemli-Opitz syndrome: A pathophysiological manifestation of the Bloch hypothesis

Chattopadhyay

Sharma²

2023

Front. Mol. Biosci.

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The biosynthesis of cholesterol, an essential component of higher eukaryotic membranes, was worked out by Konrad Bloch (and Feodor Lynen) in the 1960s and they received the Nobel Prize around that time in recognition of their pioneering contributions. An elegant consequence of this was a hypothesis proposed by Konrad Bloch (the Bloch hypothesis) which suggests that each subsequent intermediate in the cholesterol biosynthesis pathway is superior in supporting membrane function in higher eukaryotes relative to its precursor. In this review, we discuss an autosomal recessive metabolic disorder, known as Smith-Lemli-Opitz syndrome (SLOS), associated with a defect in the Kandutsch-Russell pathway of cholesterol biosynthesis that results in accumulation of the immediate precursor of cholesterol in its biosynthetic pathway (7-dehydrocholesterol) and an altered cholesterol to total sterol ratio. Patients suffering from SLOS have several developmental, behavioral and cognitive abnormalities for which no drug is available yet. We characterize SLOS as a manifestation of the Bloch hypothesis and review its molecular etiology and current treatment. We further discuss defective Hedgehog signaling in SLOS and focus on the role of the serotonin1A receptor, a representative neurotransmitter receptor belonging to the GPCR family, in SLOS. Notably, ligand binding activity and cellular signaling of serotonin1A receptors are impaired in SLOS-like condition. Importantly, cellular localization and intracellular trafficking of the serotonin1A receptor (which constitute an important determinant of a GPCR cellular function) are compromised in SLOS. We highlight some of the recent developments and emerging concepts in SLOS pathobiology and suggest that novel therapies based on trafficking defects of target receptors could provide new insight into treatment of SLOS.

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Patched 1 regulates Smoothened by controlling sterol binding to its extracellular cysteine-rich domain

Cited by 29 publications

References 78 publications

Role of cholesterol-recognition motifs in the infectivity of SARS-CoV-2 variants

Role of cholesterol-recognition motifs in the infectivity of SARS-CoV-2 variants

Two-way Dispatched function in Sonic hedgehog shedding and transfer to high-density lipoproteins

Smith-Lemli-Opitz syndrome: A pathophysiological manifestation of the Bloch hypothesis

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