Native structure of mosquito salivary protein uncovers domains relevant to pathogen transmission

Abstract

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 receptor domains on the surface of SGS1, are likely key in facilitating sporozoite/arbovirus invasion into the salivary glands and manipulating the host’s immune response.

To split or not to split: CASP15 targets and their processing into tertiary structure evaluation units

“…(A) Target T1169, a mosquito protein relevant to pathogen transmission (PDB: 8FJP) with four evaluation units defined: D1: 1–345; D2: 1302–2735; D3: 378–6991, 223–1301; D4: 700–1222. (B) Parsing of SGS1 into domains as suggested by the authors of the structure 28 . (C) Top HHsearch hits showing similarity of the query sequence to known folds in two areas: 395–670 (intermediate domain between the two beta‐propellers—see panel B) and 1718–2735 (region after the lectin‐CRD domain and up to the TM domain).…”

“…The last example is target T1169, a mosquito salivary protein SGS1 involved in mosquito‐borne diseases 28 . It is the largest monomeric target in the history of CASP (3364 residues in the sequence; 2735 residues resolved in the structure).…”

“…It has a cocoon‐shaped structure with multiple domains and extensive inter‐domain interactions (Figure 7), thus presenting a significant challenge in defining EUs. The top‐ranked SWORD/SWORD2 splitting schema suggested 7 domains; the domain definition from the authors (Figure 7B 28 ) and the results of HHsearch homology searches (Figure 7C) offered additional help in defining domains. Domains were originally defined so that the following 7 areas were separated: the N‐term β‐propeller (blue in panel A, orange in panel B), region between the two β‐propellers (HHsearch), β‐propeller 2, region after the beta‐propeller, CBM domain, lectin‐CRD domain, the area containing the wedge domain up to the TM domain (HHsearch).…”

“…DDomain classifies it into four domains (as numbered in the figure), while DomainParser and SWORD suggest a three-domain arrangement with domains 2 and 3 joined. Starting with the most disjoint 4-domain version and based on the Grishin plot analysis (B) we joined domains 2, 3 and 4 into one EU, while leaving domain 1 separate.The last example is target T1169, a mosquito salivary protein SGS1 involved in mosquito-borne diseases 28. It is the largest monomeric target in the history of CASP (3364 residues in the sequence; 2735 residues resolved in the structure).…”

To split or not to split: CASP15 targets and their processing into tertiary structure evaluation units

“…A Grishin plot for the target (not shown) supports the suggested split. The last example is target T1169, a mosquito salivary protein SGS1 involved in mosquito-borne diseases 28 . It is the largest monomeric target in the history of CASP (3364 residues in the sequence; 2735 residues resolved in the structure).…”