biostudies-literatureLiu SIntramural NIH HHSNCRR NIH HHSFoundation for the National Institutes of HealthNIGMS NIH HHSNIH HHS899https://www.ebi.ac.uk/biostudies/studies/S-EPMC9935623biostudies-literatureUnknown14(1)Female mosquitoes inject saliva into vertebrate hosts during blood feeding. This process transmits mosquito-borne human pathogens that collectively cause ~1,000,000 deaths/year. Among the most abundant and conserved proteins secreted by female salivary glands is a high-molecular weight protein called salivary gland surface protein 1 (SGS1) that facilitates pathogen transmission, but its mechanism remains elusive. Here, we determine the native structure of SGS1 by the cryoID approach, showing that the 3364 amino-acid protein has a Tc toxin-like Rhs/YD shell, four receptor domains, and a set of C-terminal daisy-chained helices. These helices are partially shielded inside the Rhs/YD shell and poised to transform into predicted transmembrane helices. This transformation, and the numerous recepNature communicationsNative structure of mosquito salivary protein uncovers domains relevant to pathogen transmission.PMC9935623R01 GM071940S10 OD018111AI001246S10 RR023057R01GM071940ZIA AI001246Zhou ZHXia XLiu SCalvo EfalseNative structure of mosquito salivary protein uncovers domains relevant to pathogen transmission.Female mosquitoes inject saliva into vertebrate hosts during blood feeding. This process transmits mosquito-borne human pathogens that collectively cause ~1,000,000 deaths/year. Among the most abundant and conserved proteins secreted by female salivary glands is a high-molecular weight protein called salivary gland surface protein 1 (SGS1) that facilitates pathogen transmission, but its mechanism remains elusive. Here, we determine the native structure of SGS1 by the cryoID approach, showing that the 3364 amino-acid protein has a Tc toxin-like Rhs/YD shell, four receptor domains, and a set of C-terminal daisy-chained helices. These helices are partially shielded inside the Rhs/YD shell and poised to transform into predicted transmembrane helices. This transformation, and the numerous recep2023-01-01T00:00:00Z2023 Feb2026-05-28T18:33:45.185Z2025-04-19T02:46:20.28ZS-EPMC99356233679729010.1038/s41467-023-36577-y