8b7d

From Proteopedia

(Difference between revisions)

Revision as of 06:11, 19 July 2023

Luminal domain of TMEM106B

Structural highlights

8b7d is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.59Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

T106B_HUMAN Progressive non-fluent aphasia;Semantic dementia;Behavioral variant of frontotemporal dementia. The gene represented in this entry acts as a disease modifier. Risk alleles confer genetic susceptibility by increasing gene expression (PubMed:20154673, PubMed:21178100). Increased expression may be the result of down-regulation of microRNA miR-132 and miR-212, that repress TMEM106B expression (PubMed:22895706). Thr-185 is a risk allele associated with lower GRN protein levels and early age at onset in GRN UP-FTD mutation carriers: it presents slower protein degradation that leads to higher steady-state TMEM106B levels, leading to alterations in the intracellular versus extracellular partitioning of GRN (PubMed:23742080).^[1] ^[2] ^[3] ^[4] The gene represented in this entry acts as a disease modifier. The disease may be caused by variants affecting the gene represented in this entry.

Function

T106B_HUMAN Involved in dendrite morphogenesis and maintenance by regulating lysosomal trafficking via its interaction with MAP6. May act by inhibiting retrograde transport of lysosomes along dendrites. Required for dendrite branching.^[5] ^[6]

Publication Abstract from PubMed

SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B, a lysosomal transmembrane protein, can serve as an alternative receptor for SARS-CoV-2 entry into angiotensin-converting enzyme 2 (ACE2)-negative cells. Spike substitution E484D increased TMEM106B binding, thereby enhancing TMEM106B-mediated entry. TMEM106B-specific monoclonal antibodies blocked SARS-CoV-2 infection, demonstrating a role of TMEM106B in viral entry. Using X-ray crystallography, cryogenic electron microscopy (cryo-EM), and hydrogen-deuterium exchange mass spectrometry (HDX-MS), we show that the luminal domain (LD) of TMEM106B engages the receptor-binding motif of SARS-CoV-2 spike. Finally, we show that TMEM106B promotes spike-mediated syncytium formation, suggesting a role of TMEM106B in viral fusion. Together, our findings identify an ACE2-independent SARS-CoV-2 infection mechanism that involves cooperative interactions with the receptors heparan sulfate and TMEM106B.

TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry.,Baggen J, Jacquemyn M, Persoons L, Vanstreels E, Pye VE, Wrobel AG, Calvaresi V, Martin SR, Roustan C, Cronin NB, Reading E, Thibaut HJ, Vercruysse T, Maes P, De Smet F, Yee A, Nivitchanyong T, Roell M, Franco-Hernandez N, Rhinn H, Mamchak AA, Ah Young-Chapon M, Brown E, Cherepanov P, Daelemans D Cell. 2023 Jul 3:S0092-8674(23)00645-1. doi: 10.1016/j.cell.2023.06.005. PMID:37421949^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Van Deerlin VM, Sleiman PM, Martinez-Lage M, Chen-Plotkin A, Wang LS, Graff-Radford NR, Dickson DW, Rademakers R, Boeve BF, Grossman M, Arnold SE, Mann DM, Pickering-Brown SM, Seelaar H, Heutink P, van Swieten JC, Murrell JR, Ghetti B, Spina S, Grafman J, Hodges J, Spillantini MG, Gilman S, Lieberman AP, Kaye JA, Woltjer RL, Bigio EH, Mesulam M, Al-Sarraj S, Troakes C, Rosenberg RN, White CL 3rd, Ferrer I, Llado A, Neumann M, Kretzschmar HA, Hulette CM, Welsh-Bohmer KA, Miller BL, Alzualde A, Lopez de Munain A, McKee AC, Gearing M, Levey AI, Lah JJ, Hardy J, Rohrer JD, Lashley T, Mackenzie IR, Feldman HH, Hamilton RL, Dekosky ST, van der Zee J, Kumar-Singh S, Van Broeckhoven C, Mayeux R, Vonsattel JP, Troncoso JC, Kril JJ, Kwok JB, Halliday GM, Bird TD, Ince PG, Shaw PJ, Cairns NJ, Morris JC, McLean CA, DeCarli C, Ellis WG, Freeman SH, Frosch MP, Growdon JH, Perl DP, Sano M, Bennett DA, Schneider JA, Beach TG, Reiman EM, Woodruff BK, Cummings J, Vinters HV, Miller CA, Chui HC, Alafuzoff I, Hartikainen P, Seilhean D, Galasko D, Masliah E, Cotman CW, Tunon MT, Martinez MC, Munoz DG, Carroll SL, Marson D, Riederer PF, Bogdanovic N, Schellenberg GD, Hakonarson H, Trojanowski JQ, Lee VM. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet. 2010 Mar;42(3):234-9. doi: 10.1038/ng.536. Epub 2010 Feb 14. PMID:20154673 doi:http://dx.doi.org/10.1038/ng.536
↑ Finch N, Carrasquillo MM, Baker M, Rutherford NJ, Coppola G, Dejesus-Hernandez M, Crook R, Hunter T, Ghidoni R, Benussi L, Crook J, Finger E, Hantanpaa KJ, Karydas AM, Sengdy P, Gonzalez J, Seeley WW, Johnson N, Beach TG, Mesulam M, Forloni G, Kertesz A, Knopman DS, Uitti R, White CL 3rd, Caselli R, Lippa C, Bigio EH, Wszolek ZK, Binetti G, Mackenzie IR, Miller BL, Boeve BF, Younkin SG, Dickson DW, Petersen RC, Graff-Radford NR, Geschwind DH, Rademakers R. TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology. 2011 Feb 1;76(5):467-74. doi: 10.1212/WNL.0b013e31820a0e3b. Epub 2010 , Dec 22. PMID:21178100 doi:http://dx.doi.org/10.1212/WNL.0b013e31820a0e3b
↑ Chen-Plotkin AS, Unger TL, Gallagher MD, Bill E, Kwong LK, Volpicelli-Daley L, Busch JI, Akle S, Grossman M, Van Deerlin V, Trojanowski JQ, Lee VM. TMEM106B, the risk gene for frontotemporal dementia, is regulated by the microRNA-132/212 cluster and affects progranulin pathways. J Neurosci. 2012 Aug 15;32(33):11213-27. doi: 10.1523/JNEUROSCI.0521-12.2012. PMID:22895706 doi:http://dx.doi.org/10.1523/JNEUROSCI.0521-12.2012
↑ Nicholson AM, Finch NA, Wojtas A, Baker MC, Perkerson RB 3rd, Castanedes-Casey M, Rousseau L, Benussi L, Binetti G, Ghidoni R, Hsiung GY, Mackenzie IR, Finger E, Boeve BF, Ertekin-Taner N, Graff-Radford NR, Dickson DW, Rademakers R. TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia. J Neurochem. 2013 Sep;126(6):781-91. doi: 10.1111/jnc.12329. Epub 2013 Jul 1. PMID:23742080 doi:http://dx.doi.org/10.1111/jnc.12329
↑ Brady OA, Zheng Y, Murphy K, Huang M, Hu F. The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Hum Mol Genet. 2013 Feb 15;22(4):685-95. doi: 10.1093/hmg/dds475. Epub 2012 Nov, 6. PMID:23136129 doi:http://dx.doi.org/10.1093/hmg/dds475
↑ Schwenk BM, Lang CM, Hogl S, Tahirovic S, Orozco D, Rentzsch K, Lichtenthaler SF, Hoogenraad CC, Capell A, Haass C, Edbauer D. The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes. EMBO J. 2014 Mar 3;33(5):450-67. doi: 10.1002/embj.201385857. Epub 2013 Dec 19. PMID:24357581 doi:http://dx.doi.org/10.1002/embj.201385857
↑ Baggen J, Jacquemyn M, Persoons L, Vanstreels E, Pye VE, Wrobel AG, Calvaresi V, Martin SR, Roustan C, Cronin NB, Reading E, Thibaut HJ, Vercruysse T, Maes P, De Smet F, Yee A, Nivitchanyong T, Roell M, Franco-Hernandez N, Rhinn H, Mamchak AA, Ah Young-Chapon M, Brown E, Cherepanov P, Daelemans D. TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry. Cell. 2023 Jul 3:S0092-8674(23)00645-1. PMID:37421949 doi:10.1016/j.cell.2023.06.005

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8b7d"

Categories: Homo sapiens | Large Structures | Cherepanov P | Pye VE | Roustan C

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8b7d is ON HOLD  until Paper Publication
+==Luminal domain of TMEM106B==
+<StructureSection load='8b7d' size='340' side='right'caption='[[8b7d]], [[Resolution|resolution]] 2.59&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8b7d]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8B7D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8B7D FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.59&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=8b7d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8b7d OCA], [https://pdbe.org/8b7d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8b7d RCSB], [https://www.ebi.ac.uk/pdbsum/8b7d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8b7d ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/T106B_HUMAN T106B_HUMAN] Progressive non-fluent aphasia;Semantic dementia;Behavioral variant of frontotemporal dementia. The gene represented in this entry acts as a disease modifier. Risk alleles confer genetic susceptibility by increasing gene expression (PubMed:20154673, PubMed:21178100). Increased expression may be the result of down-regulation of microRNA miR-132 and miR-212, that repress TMEM106B expression (PubMed:22895706). Thr-185 is a risk allele associated with lower GRN protein levels and early age at onset in GRN UP-FTD mutation carriers: it presents slower protein degradation that leads to higher steady-state TMEM106B levels, leading to alterations in the intracellular versus extracellular partitioning of GRN (PubMed:23742080).<ref>PMID:20154673</ref> <ref>PMID:21178100</ref> <ref>PMID:22895706</ref> <ref>PMID:23742080</ref>   The gene represented in this entry acts as a disease modifier.  The disease may be caused by variants affecting the gene represented in this entry.
+== Function ==
+[https://www.uniprot.org/uniprot/T106B_HUMAN T106B_HUMAN] Involved in dendrite morphogenesis and maintenance by regulating lysosomal trafficking via its interaction with MAP6. May act by inhibiting retrograde transport of lysosomes along dendrites. Required for dendrite branching.<ref>PMID:23136129</ref> <ref>PMID:24357581</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B, a lysosomal transmembrane protein, can serve as an alternative receptor for SARS-CoV-2 entry into angiotensin-converting enzyme 2 (ACE2)-negative cells. Spike substitution E484D increased TMEM106B binding, thereby enhancing TMEM106B-mediated entry. TMEM106B-specific monoclonal antibodies blocked SARS-CoV-2 infection, demonstrating a role of TMEM106B in viral entry. Using X-ray crystallography, cryogenic electron microscopy (cryo-EM), and hydrogen-deuterium exchange mass spectrometry (HDX-MS), we show that the luminal domain (LD) of TMEM106B engages the receptor-binding motif of SARS-CoV-2 spike. Finally, we show that TMEM106B promotes spike-mediated syncytium formation, suggesting a role of TMEM106B in viral fusion. Together, our findings identify an ACE2-independent SARS-CoV-2 infection mechanism that involves cooperative interactions with the receptors heparan sulfate and TMEM106B.
-Authors:
+TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry.,Baggen J, Jacquemyn M, Persoons L, Vanstreels E, Pye VE, Wrobel AG, Calvaresi V, Martin SR, Roustan C, Cronin NB, Reading E, Thibaut HJ, Vercruysse T, Maes P, De Smet F, Yee A, Nivitchanyong T, Roell M, Franco-Hernandez N, Rhinn H, Mamchak AA, Ah Young-Chapon M, Brown E, Cherepanov P, Daelemans D Cell. 2023 Jul 3:S0092-8674(23)00645-1. doi: 10.1016/j.cell.2023.06.005. PMID:37421949<ref>PMID:37421949</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 8b7d" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Cherepanov P]]
+[[Category: Pye VE]]
+[[Category: Roustan C]]

8b7d

From Proteopedia

Revision as of 06:11, 19 July 2023

Luminal domain of TMEM106B

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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