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From Proteopedia
Structural and functional insights into Hydra Actinoporin-Like Toxin 1 (HALT-1)
Structural highlights
FunctionACTL1_HYDVU Pore-forming protein that forms hydrophilic pores and causes cytolysis (PubMed:24768765, PubMed:31513812). Compared to equinatoxin-2 (AC P61914), it reveals lower cytolysis activity (5-12-fold difference, tested on erythrocytes), a larger pore size (probably 2-3 nm) and different affinity to membrane lipids (100-fold lower affinity to sphingomyelin) (PubMed:24768765). Binds to sulfatides (SFT) as well as to the two sphingolipids, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) (PubMed:31513812). It seems to bind more strongly to LPA than to S1P and SFT (PubMed:31513812). Shows cytolytic activity on HeLa cells, with a different potency than its paralogs (from most potent to less potent: HALT-4>HALT-6~HALT-1>HALT-3>HALT-7>HALT-2) (PubMed:31513812). Pore formation is a multi-step process that involves specific recognition of membrane lipid by a protein aromatic residues rich region, firm binding to the membrane (mainly driven by hydrophobic interactions) accompanied by the transfer of the N-terminal region to the lipid-water interface and finally pore formation after oligomerization of monomers (By similarity) (PubMed:31513812). In vitro, binds to the folate receptor alpha (FOLR1), a GPI-anchored membrane protein that plays a major role in the uptake of folate/folic acid into cells via endocytosis, suggesting a possible involvement of this receptor in the mechanism of HALT-1-induced cell lysis (PubMed:28478056). In vivo, does not cause visible paralysis in larvae of the blowfly Sarcophaga faculata, the most common arthropod prey of Hydra (PubMed:24768765).[UniProtKB:B9W5G6][1] [2] [3] Publication Abstract from PubMedActinoporins are a family of alpha-pore-forming toxins (alpha-PFTs) that have been identified in sea anemones. Recently, a freshwater Hydra Actinoporin-Like Toxin (HALT) gene family was found in Hydra magnipapillata. Unlike sea anemone actinoporins that use sphingomyelin as their main recognition target, the HALTs proteins may recognise alternative lipid molecules as their target. To unveil the structural insights into lipid preference of HALTs protein as compared to sea anemone actinoporins, we have determined the first crystal structure of actinoporin-like toxin, HALT-1 at 1.43 A resolution with an acetylated lysine residue K76. Despite the overall structure of HALT-1 sharing a high structural similarity to sea anemone actinoporins, the atomic resolution structure revealed several unique structural features of HALT-1 that may influence the lipid preference and oligomerisation interface. The HALT-1 contains a RAG motif in place of the highly conserved RGD motif found in sea anemone actinoporins. The RAG motif contributed to a sharper beta9-beta10 turn, which may sway its oligomerisation interface in comparison to sea anemone actinoporins. In the lipid-binding region, the HALT-1 contains a shorter alpha2 helix and a longer alpha2-beta9 loop due to deletion and subsequently an insertion of five amino acid residues in comparison to the sea anemone actinoporins. Structure comparison and molecular docking analysis further revealed that the HALT-1 lipid-binding site may favour sphingolipids with sulfate or phosphate head group more than the sphingomyelin. The structure of HALT-1 reported here provides a new insight for a better understanding of the evolution and lipid recognition mechanism of actinoporin. Structural and functional analysis of Hydra Actinoporin-Like Toxin 1 (HALT-1).,Ker DS, Sha HX, Jonet MA, Hwang JS, Ng CL Sci Rep. 2021 Oct 19;11(1):20649. doi: 10.1038/s41598-021-99879-5. PMID:34667248[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Hydra vulgaris | Large Structures | Hwang JS | Jonet MA | Ker DS | Ng CL | Sha XH
