D7r2

Summary: This annotation correctly reflects the subcellular localization of D7r2 as a secreted salivary protein. The IBA annotation is based on phylogenetic inference from the PANTHER family including D7r4 (Q7PNF2) which shares the same localization.

Reason: D7r2 is a secreted protein with a signal peptide (residues 1-21) [UniProt Q9UB31]. It is released into the extracellular space (saliva) during blood feeding. The UniProt entry confirms "SUBCELLULAR LOCATION: Secreted" (PMID:17913537) [UniProt Q9UB31]. The IBA inference is appropriate as all D7 family members share this secreted localization pattern. Deep research on the D7 family confirms "D7r1 is produced in adult female salivary glands and secreted in saliva at the skin interface during probing/feeding" [file:ANOGA/D7r1/D7r1-deep-research-falcon.md], which applies equally to D7r2.

Summary: This annotation is INCORRECT. While the IBA inference is based on structural family membership (PBP/GOBP-related proteins), D7r2 has no role in olfaction. The protein is expressed exclusively in female salivary glands, not olfactory tissues, and functions in blood feeding facilitation, not smell perception.

Reason: D7r2 belongs to the PBP/GOBP structural family (InterPro IPR006170), which includes olfactory proteins in other contexts. However, the D7 subfamily has evolutionarily repurposed this fold for binding biogenic amines in saliva to facilitate blood feeding, not for odorant detection. D7r2 is expressed exclusively in adult female salivary glands [PMID:11841502, PMID:9990055], not in olfactory tissues. It is not detected in male tissues or in embryo, larval, and pupal stages [PMID:11841502]. The UniProt function annotation explicitly states D7r2 "Modulates blood feeding of female mosquitoes on vertebrate species by binding and sequestering different mediators involved in the host response" [UniProt Q9UB31] - with no mention of olfactory function. Deep research confirms short-form D7s "predominantly bind biogenic amines (serotonin/5-HT, histamine, epinephrine/norepinephrine)" not odorants [file:ANOGA/D7r1/D7r1-deep-research-falcon.md]. The IBA inference from Drosophila odorant binding proteins (FB:FBgn0011279, FB:FBgn0034468, etc.) is inappropriate as the function has diverged in mosquito D7 proteins.

Summary: This annotation is based on structural family membership (PBP/GOBP family via InterPro IPR006170) but does not reflect the actual function of D7r2. The protein binds biogenic amines (serotonin, histamine, norepinephrine), not odorants, and has no role in olfaction.

Reason: D7r2 belongs to the PBP/GOBP structural family (InterPro IPR006170), which led to this IEA annotation via GO_REF:0000002. However, the D7 proteins have evolutionarily repurposed this fold for binding biogenic amines in saliva, not odorants in antennae. D7r2 is expressed exclusively in female salivary glands [PMID:11841502, PMID:9990055], not olfactory tissues. The actual molecular function is binding serotonin (GO:0051378), histamine (GO:0051381), and norepinephrine (GO:0051380). UniProt confirms "Binds serotonin, noradrenaline, histamine and adrenaline (PubMed:16301315)" [UniProt Q9UB31]. This is a clear case where structural homology does not predict function. The GO:0005549 definition "Binding to an odorant, any substance capable of stimulating the sense of smell" does not apply - serotonin, histamine, and norepinephrine are not odorants. Deep research confirms D7 short forms "bind serotonin, histamine, and catecholamines with high affinity" [file:ANOGA/D7r1/D7r1-deep-research-falcon.md].

Proposed replacements: serotonin binding histamine binding norepinephrine binding

Summary: This annotation correctly reflects the subcellular localization of D7r2 as a secreted salivary protein. It is appropriately broader than the more specific GO:0005615 (extracellular space) annotation.

Reason: D7r2 is a secreted protein with a signal peptide (residues 1-21) [UniProt Q9UB31]. The UniProt entry confirms "SUBCELLULAR LOCATION: Secreted" based on PMID:17913537 [UniProt Q9UB31]. It is released into the extracellular region (saliva) during blood feeding. This IEA annotation from UniProt subcellular location vocabulary mapping (GO_REF:0000044) is accurate. Deep research confirms D7 proteins are "secreted in saliva at the skin interface during probing/feeding" [file:ANOGA/D7r1/D7r1-deep-research-falcon.md].

Summary: This annotation is appropriate. D7r2 exhibits vasodilating activity by sequestering host vasoconstrictors (serotonin, norepinephrine), thereby facilitating blood feeding.

Reason: UniProt explicitly states D7r2 "Exhibits vasodilating activity (PubMed:16301315)" and "Inhibits histamine-, serotonin- and noradrenaline-induced smooth muscle contraction (PubMed:16301315)" [UniProt Q9UB31]. By sequestering serotonin and norepinephrine (which are vasoconstrictors), D7r2 effectively promotes vasodilation at the bite site. This IEA annotation inferred from the UniProt keyword "Vasodilator" (KW-0840) via GO_REF:0000043 is accurate. Deep research confirms D7 kratagonist function "counteracts platelet aggregation, vasoconstriction, and nociception during feeding" [file:ANOGA/D7r1/D7r1-deep-research-falcon.md].

Summary: This annotation is acceptable but less informative than the vasodilation annotation. D7r2 modulates blood vessel diameter by promoting vasodilation through sequestration of vasoconstrictive amines.

Reason: D7r2 affects blood vessel diameter through its vasodilating activity - by sequestering serotonin and norepinephrine (vasoconstrictors), it promotes vessel dilation at the bite site. This IEA annotation from UniProt keyword "Vasoactive" (KW-0838) via GO_REF:0000043 is technically correct. However, this is a broader, less informative term than GO:0042311 (vasodilation), which better captures the specific mechanism. The primary function is facilitating blood feeding through kratagonism, not general blood vessel maintenance. Keeping as non-core since vasodilation (GO:0042311) is the more appropriate and specific annotation.

Summary: This annotation is experimentally supported by mass spectrometry identification of D7r2 in female saliva, demonstrating its localization in the extracellular space.

Reason: PMID:17913537 (Orlandi-Pradines et al., 2007) performed proteomic analysis of Anopheles gambiae saliva using mass spectrometry and identified D7r2 as a salivary protein in female mosquitoes. The UniProt entry confirms "IDENTIFICATION BY MASS SPECTROMETRY, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY" citing PMID:17913537 [UniProt Q9UB31]. The tissue specificity annotation states "Female saliva (at protein level) (PubMed:17913537)" [UniProt Q9UB31]. This IDA annotation with direct experimental evidence is correct and more reliable than the IBA inference for the same term.

Summary: D7r2 binds serotonin with high affinity as demonstrated by direct binding assays. This is a core molecular function that should be annotated.

Reason: UniProt confirms "Binds serotonin, noradrenaline, histamine and adrenaline (PubMed:16301315)" [UniProt Q9UB31]. The protein has specific binding sites for serotonin (residues 31, 59, 118, 135, 138 based on homology to Q7PNF2) [UniProt Q9UB31]. PMID:16301315 demonstrated that "four of these five short D7 proteins and the D7 long form bind serotonin with high affinity, as well as histamine and norepinephrine" using isothermal microcalorimetry and smooth muscle bioassays [PMID:16301315]. This is the actual molecular function that enables kratagonism - sequestering host serotonin to prevent vasoconstriction. GO:0051378 definition "Binding to serotonin (5-hydroxytryptamine), a monoamine neurotransmitter" accurately describes this function. Deep research confirms D7 short forms "bind serotonin, histamine, and catecholamines with high affinity" [file:ANOGA/D7r1/D7r1-deep-research-falcon.md].

Summary: D7r2 binds histamine with high affinity as demonstrated by direct binding assays. This is a core molecular function that should be annotated.

Reason: UniProt confirms "Binds serotonin, noradrenaline, histamine and adrenaline (PubMed:16301315)" [UniProt Q9UB31]. The protein has specific binding sites for histamine (residues 118, 135, 138 based on homology to Q7PNF2) [UniProt Q9UB31]. PMID:16301315 demonstrated that short D7 proteins bind "serotonin with high affinity, as well as histamine and norepinephrine" using isothermal microcalorimetry and smooth muscle bioassays [PMID:16301315]. This is the actual molecular function that enables sequestration of host histamine to prevent inflammation and pruritus. GO:0051381 definition "Binding to histamine, a physiologically active amine" accurately describes this function. Deep research confirms short-form D7s bind "biogenic amines (serotonin/5-HT, histamine, epinephrine/norepinephrine)" [file:ANOGA/D7r1/D7r1-deep-research-falcon.md].

Summary: D7r2 binds norepinephrine (noradrenaline) with high affinity as demonstrated by direct binding assays. This is a core molecular function that should be annotated.

Reason: UniProt confirms "Binds serotonin, noradrenaline, histamine and adrenaline (PubMed:16301315)" [UniProt Q9UB31]. The protein has specific binding sites for noradrenaline (residues 31, 46, 135, 138 based on homology to Q7PNF2) [UniProt Q9UB31]. UniProt also states D7r2 "Inhibits histamine-, serotonin- and noradrenaline-induced smooth muscle contraction (PubMed:16301315)" [UniProt Q9UB31]. PMID:16301315 demonstrated that short D7 proteins bind "serotonin with high affinity, as well as histamine and norepinephrine" [PMID:16301315]. This molecular function enables sequestration of host norepinephrine to prevent vasoconstriction. GO:0051380 definition "Binding to norepinephrine... a hormone secreted by the adrenal medulla and a neurotransmitter" accurately describes this function.

Summary: D7r2 negatively regulates host hemostasis by sequestering serotonin (which promotes platelet aggregation) and other biogenic amines. This is a core biological process annotation.

Reason: By sequestering serotonin (which promotes platelet aggregation), histamine, and norepinephrine, D7r2 negatively regulates the host hemostatic response during blood feeding. PMID:16301315 explicitly states "Scavenging of host amines would antagonize their vasoconstrictor, platelet-aggregating, and pain-inducing properties" [PMID:16301315]. Deep research confirms biogenic amine scavenging "counteracts platelet aggregation, vasoconstriction, and nociception during feeding" [file:ANOGA/D7r1/D7r1-deep-research-falcon.md]. GO:1900047 definition "Any process that stops, prevents or reduces the frequency, rate or extent of hemostasis" accurately captures this function. This is a more accurate BP annotation than vague terms. Note that the D7r1 homolog hamadarin also has anticoagulant activity via contact pathway inhibition, suggesting this family broadly inhibits hemostasis [file:ANOGA/D7r1/D7r1-deep-research-falcon.md].