D7r3

Summary: This annotation is based on structural family membership (PBP/GOBP family via InterPro IPR006170) but does not reflect the actual function of D7r3. The protein binds biogenic amines (serotonin, histamine, norepinephrine, adrenaline), not odorants, and has no role in olfaction.

Reason: D7r3 belongs to the PBP/GOBP structural family (InterPro IPR006170), which led to this IEA annotation. However, the D7 proteins have evolutionarily repurposed this fold for binding biogenic amines in saliva, not odorants in antennae. D7r3 is expressed exclusively in female salivary glands [PMID:11841502, PMID:9990055], not olfactory tissues. UniProt explicitly states "Binds serotonin, noradrenaline, histamine and adrenaline" [UniProt:A0A1S4GYH9, PMID:16301315]. The actual molecular functions are serotonin binding (GO:0051378) and histamine binding (GO:0051381). 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 and histamine are not odorants. Deep research on D7 family confirms "short-form D7s (including D7r1) predominantly bind biogenic amines (serotonin/5-HT, histamine, epinephrine/norepinephrine)" [file:ANOGA/D7r1/D7r1-deep-research-falcon.md].

Proposed replacements: serotonin binding histamine binding

Summary: This annotation correctly reflects the subcellular localization of D7r3 as a secreted salivary protein. However, there is a more specific IDA annotation for extracellular space (GO:0005615) from PMID:17913537.

Reason: D7r3 is a secreted protein with a signal peptide (residues 1-21) [UniProt:A0A1S4GYH9]. It is released into the extracellular space (saliva) during blood feeding. The UniProt entry confirms "SUBCELLULAR LOCATION: Secreted" [UniProt:A0A1S4GYH9]. This is an appropriate CC annotation, though the more specific GO:0005615 (extracellular space) with IDA evidence from PMID:17913537 is also present.

Summary: This annotation captures one downstream effect of D7r3's biogenic amine scavenging activity. By sequestering serotonin and norepinephrine (vasoconstrictors), D7r3 indirectly promotes vasodilation at the feeding site.

Reason: UniProt states "Exhibits vasodilating activity" [UniProt:A0A1S4GYH9, PMID:16301315]. However, this is an indirect effect - D7r3 does not directly cause vasodilation but rather prevents vasoconstriction by scavenging host vasoconstrictive amines. The primary molecular function is binding biogenic amines (kratagonism), with vasodilation being a downstream consequence. This is acceptable as a non-core BP annotation describing the physiological outcome in the host. The deep research notes "Scavenging of host amines would antagonize their vasoconstrictor, platelet-aggregating, and pain-inducing properties" [file:ANOGA/D7r1/D7r1-deep-research-falcon.md].

Summary: This annotation is overly general. D7r3 affects blood vessel diameter indirectly by scavenging vasoconstrictive amines, but "blood vessel diameter maintenance" implies homeostatic regulation, which is not the protein's function.

Reason: GO:0097746 (blood vessel diameter maintenance) is defined as "Any process that modulates the extent or rate of blood vessel diameter change". While D7r3 does affect vascular tone by preventing vasoconstriction (through amine scavenging), calling this "maintenance" is misleading. The protein disrupts normal host vascular responses rather than maintaining them. The annotation derives from the UniProt "Vasoactive" keyword (KW-0838), but D7r3's role is specifically anti-hemostatic modulation of host physiology, not vascular homeostasis. The more accurate annotation would be vasodilation (GO:0042311) or negative regulation of vasoconstriction.

Summary: This annotation is well-supported by direct experimental evidence. PMID:17913537 identified D7r3 by mass spectrometry in female saliva, confirming its extracellular localization.

Reason: The IDA evidence from PMID:17913537 is based on proteomic identification of D7r3 in female Anopheles gambiae saliva. The publication states they performed "proteomic and immunoproteomic analysis of anopheles and Aedes saliva" and identified salivary antigens. UniProt cites this paper for "IDENTIFICATION BY MASS SPECTROMETRY, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY" [UniProt:A0A1S4GYH9]. This provides direct experimental evidence that D7r3 is present in the extracellular space (saliva). This is a core CC annotation.

Summary: D7r3 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:A0A1S4GYH9]. The protein has specific binding sites for serotonin (residues 31, 59, 118, 135, 138 by similarity to Q7PNF2). 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. PMID:16301315 explicitly tested D7 short proteins and showed "four of these five short D7 proteins and the D7 long form bind serotonin with high affinity". Deep research confirms D7 short forms "bind serotonin, histamine, and catecholamines with high affinity" [file:ANOGA/D7r1/D7r1-deep-research-falcon.md].

Summary: D7r3 binds histamine 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:A0A1S4GYH9]. The protein has specific binding sites for histamine (residues 118, 135, 138 by similarity to Q7PNF2). This is the actual molecular function that enables sequestration of host histamine to prevent inflammation. GO:0051381 definition "Binding to histamine, a physiologically active amine" accurately describes this function. The functional assay in PMID:16301315 demonstrated "Inhibits histamine-, serotonin- and noradrenaline-induced smooth muscle contraction" [UniProt:A0A1S4GYH9]. Deep research confirms short-form D7s bind "biogenic amines (serotonin/5-HT, histamine, epinephrine/norepinephrine)" [file:ANOGA/D7r1/D7r1-deep-research-falcon.md].