8ath: Difference between revisions

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== Function ==
== Function ==
[https://www.uniprot.org/uniprot/LAMP1_HUMAN LAMP1_HUMAN] Lysosomal membrane glycoprotein which plays an important role in lysosome biogenesis, autophagy, and cholesterol homeostasis (By similarity). Also plays an important role in NK-cells cytotoxicity (PubMed:23632890, PubMed:2022921). Mechanistically, participates in cytotoxic granule movement to the cell surface and perforin trafficking to the lytic granule (PubMed:23632890). In addition, protects NK-cells from degranulation-associated damage induced by their own cytotoxic granule content (PubMed:23847195). Presents carbohydrate ligands to selectins. Also implicated in tumor cell metastasis.[UniProtKB:P11438]<ref>PMID:2022921</ref> <ref>PMID:23632890</ref> <ref>PMID:23847195</ref>  (Microbial infection) Acts as a receptor for Lassa virus glycoprotein (PubMed:24970085, PubMed:25972533, PubMed:27605678, PubMed:28448640). Promotes also fusion of the virus with host membrane in less acidic endosomes (PubMed:29295909).<ref>PMID:24970085</ref> <ref>PMID:25972533</ref> <ref>PMID:27605678</ref> <ref>PMID:28448640</ref> <ref>PMID:29295909</ref>  (Microbial infection) Supports the FURIN-mediated cleavage of mumps virus fusion protein F by interacting with both FURIN and the unprocessed form but not the processed form of the viral protein F.<ref>PMID:32295904</ref>  
[https://www.uniprot.org/uniprot/LAMP1_HUMAN LAMP1_HUMAN] Lysosomal membrane glycoprotein which plays an important role in lysosome biogenesis, lysosomal pH regulation, autophagy and cholesterol homeostasis (PubMed:37390818). Acts as an important regulator of lysosomal lumen pH regulation by acting as a direct inhibitor of the proton channel TMEM175, facilitating lysosomal acidification for optimal hydrolase activity (PubMed:37390818). Also plays an important role in NK-cells cytotoxicity (PubMed:2022921, PubMed:23632890). Mechanistically, participates in cytotoxic granule movement to the cell surface and perforin trafficking to the lytic granule (PubMed:23632890). In addition, protects NK-cells from degranulation-associated damage induced by their own cytotoxic granule content (PubMed:23847195). Presents carbohydrate ligands to selectins (PubMed:7685349).<ref>PMID:2022921</ref> <ref>PMID:23632890</ref> <ref>PMID:23847195</ref> <ref>PMID:37390818</ref> <ref>PMID:7685349</ref>  (Microbial infection) Acts as a receptor for Lassa virus glycoprotein (PubMed:24970085, PubMed:25972533, PubMed:27605678, PubMed:28448640). Promotes also fusion of the virus with host membrane in less acidic endosomes (PubMed:29295909).<ref>PMID:24970085</ref> <ref>PMID:25972533</ref> <ref>PMID:27605678</ref> <ref>PMID:28448640</ref> <ref>PMID:29295909</ref>  (Microbial infection) Supports the FURIN-mediated cleavage of mumps virus fusion protein F by interacting with both FURIN and the unprocessed form but not the processed form of the viral protein F.<ref>PMID:32295904</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Delineating the precise regions on an antigen that are targeted by antibodies has become a key step for the development of antibody therapeutics. X-ray crystallography and cryogenic electron microscopy are considered the gold standard for providing precise information about these binding sites at atomic resolution. However, they are labor-intensive and a successful outcome is not guaranteed. We used deep mutational scanning (DMS) of the human LAMP-1 antigen displayed on yeast surface and leveraged next-generation sequencing to observe the effect of individual mutants on the binding of two LAMP-1 antibodies and to determine their functional epitopes on LAMP-1. Fine-tuned epitope mapping by DMS approaches is augmented by knowledge of experimental antigen structure. As human LAMP-1 structure has not yet been solved, we used the AlphaFold predicted structure of the full-length protein to combine with DMS data and ultimately finely map antibody epitopes. The accuracy of this method was confirmed by comparing the results to the co-crystal structure of one of the two antibodies with a LAMP-1 luminal domain. Finally, we used AlphaFold models of non-human LAMP-1 to understand the lack of mAb cross-reactivity. While both epitopes in the murine form exhibit multiple mutations in comparison to human LAMP-1, only one and two mutations in the Macaca form suffice to hinder the recognition by mAb B and A, respectively. Altogether, this study promotes a new application of AlphaFold to speed up precision mapping of antibody-antigen interactions and consequently accelerate antibody engineering for optimization.
 
Deciphering cross-species reactivity of LAMP-1 antibodies using deep mutational epitope mapping and AlphaFold.,Pruvost T, Mathieu M, Dubois S, Maillere B, Vigne E, Nozach H MAbs. 2023 Jan-Dec;15(1):2175311. doi: 10.1080/19420862.2023.2175311. PMID:36797224<ref>PMID:36797224</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8ath" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>

Latest revision as of 14:54, 23 October 2024

CRYSTAL STRUCTURE OF LAMP1 IN COMPLEX WITH FAB-B.CRYSTAL STRUCTURE OF LAMP1 IN COMPLEX WITH FAB-B.

Structural highlights

8ath is a 6 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 2.366Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LAMP1_HUMAN Lysosomal membrane glycoprotein which plays an important role in lysosome biogenesis, lysosomal pH regulation, autophagy and cholesterol homeostasis (PubMed:37390818). Acts as an important regulator of lysosomal lumen pH regulation by acting as a direct inhibitor of the proton channel TMEM175, facilitating lysosomal acidification for optimal hydrolase activity (PubMed:37390818). Also plays an important role in NK-cells cytotoxicity (PubMed:2022921, PubMed:23632890). Mechanistically, participates in cytotoxic granule movement to the cell surface and perforin trafficking to the lytic granule (PubMed:23632890). In addition, protects NK-cells from degranulation-associated damage induced by their own cytotoxic granule content (PubMed:23847195). Presents carbohydrate ligands to selectins (PubMed:7685349).[1] [2] [3] [4] [5] (Microbial infection) Acts as a receptor for Lassa virus glycoprotein (PubMed:24970085, PubMed:25972533, PubMed:27605678, PubMed:28448640). Promotes also fusion of the virus with host membrane in less acidic endosomes (PubMed:29295909).[6] [7] [8] [9] [10] (Microbial infection) Supports the FURIN-mediated cleavage of mumps virus fusion protein F by interacting with both FURIN and the unprocessed form but not the processed form of the viral protein F.[11]

Publication Abstract from PubMed

Delineating the precise regions on an antigen that are targeted by antibodies has become a key step for the development of antibody therapeutics. X-ray crystallography and cryogenic electron microscopy are considered the gold standard for providing precise information about these binding sites at atomic resolution. However, they are labor-intensive and a successful outcome is not guaranteed. We used deep mutational scanning (DMS) of the human LAMP-1 antigen displayed on yeast surface and leveraged next-generation sequencing to observe the effect of individual mutants on the binding of two LAMP-1 antibodies and to determine their functional epitopes on LAMP-1. Fine-tuned epitope mapping by DMS approaches is augmented by knowledge of experimental antigen structure. As human LAMP-1 structure has not yet been solved, we used the AlphaFold predicted structure of the full-length protein to combine with DMS data and ultimately finely map antibody epitopes. The accuracy of this method was confirmed by comparing the results to the co-crystal structure of one of the two antibodies with a LAMP-1 luminal domain. Finally, we used AlphaFold models of non-human LAMP-1 to understand the lack of mAb cross-reactivity. While both epitopes in the murine form exhibit multiple mutations in comparison to human LAMP-1, only one and two mutations in the Macaca form suffice to hinder the recognition by mAb B and A, respectively. Altogether, this study promotes a new application of AlphaFold to speed up precision mapping of antibody-antigen interactions and consequently accelerate antibody engineering for optimization.

Deciphering cross-species reactivity of LAMP-1 antibodies using deep mutational epitope mapping and AlphaFold.,Pruvost T, Mathieu M, Dubois S, Maillere B, Vigne E, Nozach H MAbs. 2023 Jan-Dec;15(1):2175311. doi: 10.1080/19420862.2023.2175311. PMID:36797224[12]

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

References

  1. ↑ Peters PJ, Borst J, Oorschot V, Fukuda M, Krähenbühl O, Tschopp J, Slot JW, Geuze HJ. Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. J Exp Med. 1991 May 1;173(5):1099-109. PMID:2022921 doi:10.1084/jem.173.5.1099
  2. ↑ Krzewski K, Gil-Krzewska A, Nguyen V, Peruzzi G, Coligan JE. LAMP1/CD107a is required for efficient perforin delivery to lytic granules and NK-cell cytotoxicity. Blood. 2013 Jun 6;121(23):4672-83. PMID:23632890 doi:10.1182/blood-2012-08-453738
  3. ↑ Cohnen A, Chiang SC, Stojanovic A, Schmidt H, Claus M, Saftig P, Janßen O, Cerwenka A, Bryceson YT, Watzl C. Surface CD107a/LAMP-1 protects natural killer cells from degranulation-associated damage. Blood. 2013 Aug 22;122(8):1411-8. PMID:23847195 doi:10.1182/blood-2012-07-441832
  4. ↑ Zhang J, Zeng W, Han Y, Lee WR, Liou J, Jiang Y. Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the TMEM175 channel. Mol Cell. 2023 Jul 20;83(14):2524-2539.e7. PMID:37390818 doi:10.1016/j.molcel.2023.06.004
  5. ↑ Sawada R, Lowe JB, Fukuda M. E-selectin-dependent adhesion efficiency of colonic carcinoma cells is increased by genetic manipulation of their cell surface lysosomal membrane glycoprotein-1 expression levels. J Biol Chem. 1993 Jun 15;268(17):12675-81 PMID:7685349
  6. ↑ Jae LT, Raaben M, Herbert AS, Kuehne AI, Wirchnianski AS, Soh TK, Stubbs SH, Janssen H, Damme M, Saftig P, Whelan SP, Dye JM, Brummelkamp TR. Virus entry. Lassa virus entry requires a trigger-induced receptor switch. Science. 2014 Jun 27;344(6191):1506-10. doi: 10.1126/science.1252480. PMID:24970085 doi:http://dx.doi.org/10.1126/science.1252480
  7. ↑ Cohen-Dvashi H, Cohen N, Israeli H, Diskin R. Molecular mechanism for LAMP1 recognition by Lassa Virus. J Virol. 2015 May 13. pii: JVI.00651-15. PMID:25972533 doi:http://dx.doi.org/10.1128/JVI.00651-15
  8. ↑ Cohen-Dvashi H, Israeli H, Shani O, Katz A, Diskin R. Role of LAMP1 Binding and pH Sensing by the Spike Complex of Lassa Virus. J Virol. 2016 Oct 28;90(22):10329-10338. Print 2016 Nov 15. PMID:27605678 doi:http://dx.doi.org/10.1128/JVI.01624-16
  9. ↑ Israeli H, Cohen-Dvashi H, Shulman A, Shimon A, Diskin R. Mapping of the Lassa virus LAMP1 binding site reveals unique determinants not shared by other old world arenaviruses. PLoS Pathog. 2017 Apr 27;13(4):e1006337. doi: 10.1371/journal.ppat.1006337., eCollection 2017 Apr. PMID:28448640 doi:http://dx.doi.org/10.1371/journal.ppat.1006337
  10. ↑ Hulseberg CE, Fénéant L, Szymańska KM, White JM. Lamp1 Increases the Efficiency of Lassa Virus Infection by Promoting Fusion in Less Acidic Endosomal Compartments. mBio. 2018 Jan 2;9(1):e01818-17. PMID:29295909 doi:10.1128/mBio.01818-17
  11. ↑ Ueo A, Kubota M, Shirogane Y, Ohno S, Hashiguchi T, Yanagi Y. Lysosome-Associated Membrane Proteins Support the Furin-Mediated Processing of the Mumps Virus Fusion Protein. J Virol. 2020 Jun 1;94(12):e00050-20. PMID:32295904 doi:10.1128/JVI.00050-20
  12. ↑ Pruvost T, Mathieu M, Dubois S, Maillère B, Vigne E, Nozach H. Deciphering cross-species reactivity of LAMP-1 antibodies using deep mutational epitope mapping and AlphaFold. MAbs. 2023 Jan-Dec;15(1):2175311. PMID:36797224 doi:10.1080/19420862.2023.2175311

8ath, resolution 2.37Å

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