OCA at 06:04, 26 October 2022

OCA — Wed, 26 Oct 2022 06:04:42 GMT

←Older revision		Revision as of 06:04, 26 October 2022
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-	'''Unreleased structure'''

-	~~The entry~~ 7ui5 is ~~ON HOLD until Paper~~ Publication	+	==Evolution avoids a pathological stabilizing interaction in the immune protein S100A9==
		+	<StructureSection load='7ui5' size='340' side='right'caption='[[7ui5]]' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[7ui5]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7UI5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UI5 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7ui5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ui5 OCA], [https://pdbe.org/7ui5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ui5 RCSB], [https://www.ebi.ac.uk/pdbsum/7ui5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ui5 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/S10A9_HUMAN S10A9_HUMAN] S100A9 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response. It can induce neutrophil chemotaxis, adhesion, can increase the bactericidal activity of neutrophils by promoting phagocytosis via activation of SYK, PI3K/AKT, and ERK1/2 and can induce degranulation of neutrophils by a MAPK-dependent mechanism. Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions. The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase. Activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transfering arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX. The extracellular functions involve proinfammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its proinflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration. Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the proinflammatory cascade. Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth. Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3. Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK. Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants. Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread.<ref>PMID:8423249</ref> <ref>PMID:12626582</ref> <ref>PMID:15331440</ref> <ref>PMID:15598812</ref> <ref>PMID:15642721</ref> <ref>PMID:16258195</ref> <ref>PMID:19534726</ref> <ref>PMID:19087201</ref> <ref>PMID:19122197</ref> <ref>PMID:19402754</ref> <ref>PMID:19935772</ref> <ref>PMID:20103766</ref> <ref>PMID:21325622</ref> <ref>PMID:22804476</ref> <ref>PMID:21487906</ref> <ref>PMID:22808130</ref> <ref>PMID:22363402</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Stability constrains evolution. While much is known about constraints on destabilizing mutations, less is known about the constraints on stabilizing mutations. We recently identified a mutation in the innate immune protein S100A9 that provides insight into such constraints. When introduced into human S100A9, M63F simultaneously increases the stability of the protein and disrupts its natural ability to activate Toll-like receptor 4. Using chemical denaturation, we found that M63F stabilizes a calcium-bound conformation of hS100A9. We then used NMR to solve the structure of the mutant protein, revealing that the mutation distorts the hydrophobic binding surface of hS100A9, explaining its deleterious effect on function. Hydrogen-deuterium exchange (HDX) experiments revealed stabilization of the region around M63F in the structure, notably Phe37. In the structure of the M63F mutant, the Phe37 and Phe63 sidechains are in contact, plausibly forming an edge-face pi-stack. Mutating Phe37 to Leu abolished the stabilizing effect of M63F as probed by both chemical denaturation and HDX. It also restored the biological activity of S100A9 disrupted by M63F. These findings reveal that Phe63 creates a molecular staple with Phe37 that stabilizes a nonfunctional conformation of the protein, thus disrupting function. Using a bioinformatic analysis, we found that S100A9 proteins from different organisms rarely have Phe at both positions 37 and 63, suggesting that avoiding a pathological stabilizing interaction indeed constrains S100A9 evolution. This work highlights an important evolutionary constraint on stabilizing mutations, namely, that they must avoid inappropriately stabilizing nonfunctional protein conformations.

-	~~Authors: Reardon, P.N~~., Harman, ~~J.L.~~, Costello~~, S.M.~~, Warren~~, G.D.~~, Phillips~~, S.R.~~, Connor~~, P.J.~~, Marqusee, S., ~~Harms, M~~.J.	+	Evolution avoids a pathological stabilizing interaction in the immune protein S100A9.,Harman JL, Reardon PN, Costello SM, Warren GD, Phillips SR, Connor PJ, Marqusee S, Harms MJ Proc Natl Acad Sci U S A. 2022 Oct 11;119(41):e2208029119. doi:, 10.1073/pnas.2208029119. Epub 2022 Oct 4. PMID:36194634<ref>PMID:36194634</ref>

-	~~Description: Evolution avoids~~ a ~~pathological stabilizing interaction in~~ the ~~immune protein S100A9~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: ~~Phillips, S.R~~]]	+	<div class="pdbe-citations 7ui5" style="background-color:#fffaf0;"></div>
-	[[Category: Connor~~, P.J~~]]	+	== References ==
-	[[Category: ~~Harman, J.L~~]]	+	<references/>
-	[[Category: ~~Costello, S.M~~]]	+	__TOC__
-	[[Category: ~~Warren, G.D~~]]	+	</StructureSection>
-	[[Category: Marqusee, S]]	+	[[Category: Homo sapiens]]
-	[[Category: Reardon~~, P.N~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Harms, M.J~~]]	+	[[Category: Connor PJ]]
		+	[[Category: Costello SM]]
		+	[[Category: Harman JL]]
		+	[[Category: Harms MJ]]
		+	[[Category: Marqusee S]]
		+	[[Category: Phillips SR]]
		+	[[Category: Reardon PN]]
		+	[[Category: Warren GD]]

OCA at 11:29, 4 May 2022

OCA — Wed, 04 May 2022 11:29:32 GMT

←Older revision		Revision as of 11:29, 4 May 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7ui5 is ON HOLD	+	The entry 7ui5 is ON HOLD until Paper Publication

	Authors: Reardon, P.N., Harman, J.L., Costello, S.M., Warren, G.D., Phillips, S.R., Connor, P.J., Marqusee, S., Harms, M.J.		Authors: Reardon, P.N., Harman, J.L., Costello, S.M., Warren, G.D., Phillips, S.R., Connor, P.J., Marqusee, S., Harms, M.J.
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	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Phillips, S.R]]		[[Category: Phillips, S.R]]
		+	[[Category: Connor, P.J]]
		+	[[Category: Harman, J.L]]
		+	[[Category: Costello, S.M]]
	[[Category: Warren, G.D]]		[[Category: Warren, G.D]]
	[[Category: Marqusee, S]]		[[Category: Marqusee, S]]
	[[Category: Reardon, P.N]]		[[Category: Reardon, P.N]]
	[[Category: Harms, M.J]]		[[Category: Harms, M.J]]
-	[[Category: Connor, P.J]]
-	[[Category: Harman, J.L]]
-	[[Category: Costello, S.M]]

OCA: Protected "7ui5" [edit=sysop:move=sysop]

OCA — Wed, 06 Apr 2022 09:05:16 GMT

Protected "7ui5" [edit=sysop:move=sysop]

←Older revision

Revision as of 09:05, 6 April 2022

OCA: New page: '''Unreleased structure''' The entry 7ui5 is ON HOLD Authors: Reardon, P.N., Harman, J.L., Costello, S.M., Warren, G.D., Phillips, S.R., Connor, P.J., Marqusee, S., Harms, M.J. Descrip...

OCA — Wed, 06 Apr 2022 09:05:15 GMT

New page: '''Unreleased structure''' The entry 7ui5 is ON HOLD Authors: Reardon, P.N., Harman, J.L., Costello, S.M., Warren, G.D., Phillips, S.R., Connor, P.J., Marqusee, S., Harms, M.J. Descrip...

New page

'''Unreleased structure'''

The entry 7ui5 is ON HOLD

Authors: Reardon, P.N., Harman, J.L., Costello, S.M., Warren, G.D., Phillips, S.R., Connor, P.J., Marqusee, S., Harms, M.J.

Description: Evolution avoids a pathological stabilizing interaction in the immune protein S100A9
[[Category: Unreleased Structures]]
[[Category: Phillips, S.R]]
[[Category: Warren, G.D]]
[[Category: Marqusee, S]]
[[Category: Reardon, P.N]]
[[Category: Harms, M.J]]
[[Category: Connor, P.J]]
[[Category: Harman, J.L]]
[[Category: Costello, S.M]]

7ui5 - Revision history

OCA at 06:04, 26 October 2022

OCA at 11:29, 4 May 2022

OCA: Protected "7ui5" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 7ui5 is ON HOLD Authors: Reardon, P.N., Harman, J.L., Costello, S.M., Warren, G.D., Phillips, S.R., Connor, P.J., Marqusee, S., Harms, M.J. Descrip...