2022
DOI: 10.1038/s42003-022-03883-y
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SPACA6 ectodomain structure reveals a conserved superfamily of gamete fusion-associated proteins

Abstract: SPACA6 is a sperm-expressed surface protein that is critical for gamete fusion during mammalian sexual reproduction. Despite this fundamental role, little is known about how SPACA6 specifically functions. We elucidated the crystal structure of the SPACA6 ectodomain at 2.2-Å resolution, revealing a two-domain protein containing a four-helix bundle and Ig-like β-sandwich connected via a quasi-flexible linker. This structure is reminiscent of IZUMO1, another gamete fusion-associated protein, making SPACA6 and IZU… Show more

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Cited by 15 publications
(13 citation statements)
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“…Considering that IZUMO1-4, SPACA6, and TMEM95 are part of a distinct superfamily of extracellular proteins implicated in gamete fusion (Lamas-Toranzo et al, 2020; Nishimura et al, 2016; Vance et al, 2022) , we used Foldseek (van Kempen et al, 2023) to scan the AlphaFold/Swiss-Prot database for further proteins of similar structure. Despite insignificant sequence identities (16-27%), this search also identified transmembrane protein 81 (TMEM81) as a clear structural homolog of the conserved immunoglobulin (Ig)-like domain of IZUMO1 and SPACA6 (E-values 1.40e-8 - 1.39e-6) ( Figure 3A, B ).…”
Section: Resultsmentioning
confidence: 99%
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“…Considering that IZUMO1-4, SPACA6, and TMEM95 are part of a distinct superfamily of extracellular proteins implicated in gamete fusion (Lamas-Toranzo et al, 2020; Nishimura et al, 2016; Vance et al, 2022) , we used Foldseek (van Kempen et al, 2023) to scan the AlphaFold/Swiss-Prot database for further proteins of similar structure. Despite insignificant sequence identities (16-27%), this search also identified transmembrane protein 81 (TMEM81) as a clear structural homolog of the conserved immunoglobulin (Ig)-like domain of IZUMO1 and SPACA6 (E-values 1.40e-8 - 1.39e-6) ( Figure 3A, B ).…”
Section: Resultsmentioning
confidence: 99%
“…( A ) Structural superposition of the ectodomains of human IZUMO1 (residues C22-K255 of PDB 5JK9 chain A (Aydin et al, 2016) ), human SPACA6 (residues C27-G246 of PDB 7TA2 (Vance et al, 2022) ) and an AlphaFold model of the ectodomain of human TMEM81 (corresponding to residues I31-P218 of UniProt entry Q6P7N7). The three different regions of IZUMO1 and SPACA6 are indicated in black.…”
Section: Resultsmentioning
confidence: 99%
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“…Similarly, HAP2 is homologous with viral class II fusion proteins and maintains this ancestral role in mediating gamete membrane fusion in multiple taxa 2 , 42 44 , yet its divergent membrane insertion loops have undergone structural changes between flowering plants and trypanosomes 45 . IZUMO1, SPACA6, and TMEM95 each contain an immunoglobulin-like domain in addition to a 4-helix bundle—a structural fold that places them into a conserved superfamily of fertilization-associated proteins in vertebrates 46 , 47 . Spe-45 in C. elegans shares structural and functional homology with mouse IZUMO1 48 , 49 , while the plant sperm membrane protein GEX2 and Chlamydomonas gamete attachment protein FUS1 as well as HAP2 contain domains which also adopt Ig-like folds, underscoring the broad conservation of this structural feature in fertilization proteins 50 52 .…”
Section: Discussionmentioning
confidence: 99%