7rtc - Revision history

OCA at 11:27, 23 October 2024

2024-10-23T11:27:50Z

← Older revision		Revision as of 11:27, 23 October 2024
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	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/SARM1_DROME SARM1_DROME] NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism (PubMed:22678360, PubMed:28334607). Acts as a negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway by promoting Wallerian degeneration, an injury-induced form of programmed subcellular death which involves degeneration of an axon distal to the injury site (PubMed:22678360). Wallerian degeneration is triggered by NAD(+) depletion: in response to injury, it is activated and catalyzes cleavage of NAD(+) into ADP-D-ribose (ADPR), cyclic ADPR (cADPR) and nicotinamide; NAD(+) cleavage promoting axon destruction (PubMed:22678360, PubMed:28334607, PubMed:31439792). Involved in the down-regulation of the tracheal immune response to Gram-negative bacteria (PubMed:22022271). This is likely by mediating Tollo signaling in the tracheal epithelium (PubMed:22022271).<ref>PMID:22022271</ref> <ref>PMID:22678360</ref> <ref>PMID:28334607</ref> <ref>PMID:31439792</ref>		[https://www.uniprot.org/uniprot/SARM1_DROME SARM1_DROME] NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism (PubMed:22678360, PubMed:28334607). Acts as a negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway by promoting Wallerian degeneration, an injury-induced form of programmed subcellular death which involves degeneration of an axon distal to the injury site (PubMed:22678360). Wallerian degeneration is triggered by NAD(+) depletion: in response to injury, it is activated and catalyzes cleavage of NAD(+) into ADP-D-ribose (ADPR), cyclic ADPR (cADPR) and nicotinamide; NAD(+) cleavage promoting axon destruction (PubMed:22678360, PubMed:28334607, PubMed:31439792). Involved in the down-regulation of the tracheal immune response to Gram-negative bacteria (PubMed:22022271). This is likely by mediating Tollo signaling in the tracheal epithelium (PubMed:22022271).<ref>PMID:22022271</ref> <ref>PMID:22678360</ref> <ref>PMID:28334607</ref> <ref>PMID:31439792</ref>
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			== Publication Abstract from PubMed ==
			SARM1 is an inducible NAD(+) hydrolase that is the central executioner of pathological axon loss. Recently, we elucidated the molecular mechanism of SARM1 activation, demonstrating that SARM1 is a metabolic sensor regulated by the levels of NAD(+) and its precursor, nicotinamide mononucleotide (NMN), via their competitive binding to an allosteric site within the SARM1 N-terminal ARM domain. In healthy neurons with abundant NAD(+), binding of NAD(+) blocks access of NMN to this allosteric site. However, with injury or disease the levels of the NAD(+) biosynthetic enzyme NMNAT2 drop, increasing the NMN/ NAD(+) ratio and thereby promoting NMN binding to the SARM1 allosteric site, which in turn induces a conformational change activating the SARM1 NAD(+) hydrolase. Hence, NAD(+) metabolites both regulate the activation of SARM1 and, in turn, are regulated by the SARM1 NAD(+) hydrolase. This dual upstream and downstream role for NAD(+) metabolites in SARM1 function has hindered mechanistic understanding of axoprotective mechanisms that manipulate the NAD(+) metabolome. Here we reevaluate two methods that potently block axon degeneration via modulation of NAD(+) related metabolites, 1) the administration of the NMN biosynthesis inhibitor FK866 in conjunction with the NAD(+) precursor nicotinic acid riboside (NaR) and 2) the neuronal expression of the bacterial enzyme NMN deamidase. We find that these approaches not only lead to a decrease in the levels of the SARM1 activator NMN, but also an increase in the levels of the NAD(+) precursor nicotinic acid mononucleotide (NaMN). We show that NaMN inhibits SARM1 activation, and demonstrate that this NaMN-mediated inhibition is important for the long-term axon protection induced by these treatments. Analysis of the NaMN-ARM domain co-crystal structure shows that NaMN competes with NMN for binding to the SARM1 allosteric site and promotes the open, autoinhibited configuration of SARM1 ARM domain. Together, these results demonstrate that the SARM1 allosteric pocket can bind a diverse set of metabolites including NMN, NAD(+), and NaMN to monitor cellular NAD(+) homeostasis and regulate SARM1 NAD(+) hydrolase activity. The relative promiscuity of the allosteric site may enable the development of potent pharmacological inhibitors of SARM1 activation for the treatment of neurodegenerative disorders.

			Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection.,Sasaki Y, Zhu J, Shi Y, Gu W, Kobe B, Ve T, DiAntonio A, Milbrandt J Exp Neurol. 2021 Nov;345:113842. doi: 10.1016/j.expneurol.2021.113842. Epub 2021 , Aug 14. PMID:34403688<ref>PMID:34403688</ref>

			From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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			<div class="pdbe-citations 7rtc" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 16:38, 18 October 2023

2023-10-18T16:38:33Z

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-The entry 7rtc is ON HOLD
+==Crystal structure of the ARM domain from Drosophila SARM1 in complex with NaMN==
-Authors:
+==See Also==
+*[[SARM1 3D structures|SARM1 3D structures]]
-Description:
+== References ==
-[[Category: Unreleased Structures]]
+<references/>

OCA: Protected "7rtc" [edit=sysop:move=sysop]

2021-08-18T05:12:43Z

Protected "7rtc" [edit=sysop:move=sysop]

← Older revision	Revision as of 05:12, 18 August 2021
(No difference)

OCA: New page: '''Unreleased structure''' The entry 7rtc is ON HOLD Authors: Description: Category: Unreleased Structures

2021-08-18T05:12:42Z

New page: '''Unreleased structure''' The entry 7rtc is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 7rtc is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]