Kurtz (krz) — Drosophila melanogaster non-visual (β-)arrestin — review notes

UniProt: Q9V393 (Q9V393_DROME) · FlyBase: FBgn0040206 · CG1487 · 470 aa.

Gene identity / architecture

• Krz is the single non-visual β-arrestin of Drosophila. UniProt: "Belongs to the arrestin family"; two arrestin domains (Arrestin_N PF00339, Arrestin_C PF02752), PANTHER PTHR11792:SF17 "KURTZ ARRESTIN". Synonym beta-arr2.
• Molnar et al. frame it clearly: "In Drosophila melanogaster there is only a single non-visual β-arrestin, encoded by kurtz (krz), which function is essential for development, survival and neural function" PMID:21437272. A related gene CG32683 "lacks the clathrin-binding domain" and cannot substitute for Krz.
• Krz "has all the molecular features of a canonical β-arrestin"; conserved residues implicated in GPCR→clathrin-coated-pit targeting (Val94) and in clathrin binding (Leu440/IsoLeu441/Leu443) are functionally required PMID:21437272.

Molecular function — canonical arrestin core

• Canonical arrestin pathway restated in the Hh paper's intro: agonist-activated GPCRs are phosphorylated by GRKs, "followed by binding of the cytosolic arrestin proteins," and "the GRK/ß-arrestin pathway facilitates receptor internalization from the cell surface through clathrin-coated pits," leading to receptor degradation/recycling PMID:21437272.
• Krz "has recently been shown to promote internalization of GPCRs on receptor activation" PMID:20802461 (citing Johnson et al. 2008), and "controls Drosophila olfaction, behaviour, sensitivity to osmotic stress" PMID:20802461 — i.e. bona fide GPCR-regulator behaviour.
• Direct receptor binding demonstrated for the GPCR-family receptor Smoothened: co-IP shows Krz–Smo interaction; "these results... suggest that Krz binds to Smo and internalizes it via clathrin-coated vesicles" PMID:21437272.

MAP-kinase (ERK) sequestration — a distinctive Krz molecular function

• Krz directly binds ERK (rolled). "Krz can directly bind and sequester an inactive form of ERK, thus preventing its activation by the upstream kinase, MEK" PMID:20802461. IntAct records the Krz–rl interaction with NbExp=12 (UniProt Q9V393 INTERACTION block). This is the basis of one of the two bare GO:0005515 protein binding IPI rows from PMID:20802461 (the row whose WITH/FROM is rolled/ERK) → should be an informative MF (mitogen-activated protein kinase binding, GO:0051019). The second IPI row from the same paper has WITH/FROM = UniProtKB:Q03017 (Cactus) and is handled separately, below.
• Consequence: "loss of krz function results in an overall increase in ERK activity" PMID:20802461 → negative regulation of the MAPK cascade (rolled/ERK) and of the Torso RTK pathway.

Biological processes (mostly pleiotropic developmental-signalling roles)

• Torso (RTK) / MAPK: "the normal function of Krz is to limit the activity of ERK, and hence the Torso pathway, in the early embryo" PMID:20802461. Distinct from Notch mechanism; a "molecular sponge" sequestering inactive ERK.
• Toll / NF-κB (Dorsal–Cactus): "Krz functions during normal development to limit the activity of Toll" PMID:20802461; Krz binds and stabilises Cactus (IκBα orthologue). Independently, in the immune/larval context "Loss of function of krz or Ulp1 in Drosophila larvae results in a similar inflammatory phenotype" PMID:24077307 — Krz limits Toll signalling via the SUMO protease Ulp1.
• Hedgehog / Smoothened: over-expressed Krz promotes Smo internalization and degradation, "in a clathrin- and proteosomal-dependent manner" PMID:21437272; "Krz enhances Smo degradation via the proteosomal pathway" (protein destabilization). Antagonism of Hh is "only observed upon its over-expression" PMID:21437272; loss-of-function has no Smo phenotype (Smo unchanged in krz clones). In Cheng et al., "overexpression of Gprk2 or the β-arrestin orthologue Krz led to a reduction of Smo levels" — "first evidence that arrestins participate in Smo regulation in flies" PMID:19850026, though "Smo levels were unchanged in krz mutant wing disc clones."
• SUMO/Smo: Krz promotes Smo desumoylation by bridging Smo to Ulp1: "Krz likely facilitates the interaction between Smo and Ulp1 because knockdown of Krz by RNAi attenuates Smo-Ulp1 interaction"; "inhibits Smo sumoylation and prevents Smo accumulation through Krz regulatory domain" PMID:28195188.
• Notch: trimeric Notch–Deltex–Krz complex; "This complex mediates the degradation of the Notch receptor through a ubiquitination-dependent pathway" PMID:16284625 (abstract-only cache; IGI + Reactome R-DME-2071846 "Deltex recruits Kurtz arrestin to Notch", R-NUL-2071858 "Kurtz promotes ubiquitination of Notch").
• Behaviour / sensory: "There is a specific requirement for the kurtz nonvisual arrestin in the nervous system for both the exploration stimulated by the novel arena and the mechanically stimulated activity" PMID:17151232; Krz essential for CNS/neural function and viability PMID:21437272.

Localization

• Predominantly cytoplasmic: "the Krz protein is expressed throughout the blastoderm embryo and is predominantly cytoplasmic" PMID:20802461; "the protein is localized in the cytoplasm of imaginal cells, being detected at higher levels close to the apical side of the epithelium" PMID:21437272. Consistent with cytoplasm/cytosol (IBA, IDA, Reactome TAS). Functions transiently at the plasma membrane/endosome during receptor internalization but no dedicated experimental CC annotation for those compartments in GOA.

Curation synthesis

• Core (canonical, evolutionarily conserved arrestin functions): GPCR binding (GO:0001664), GPCR internalization (GO:0002031), positive regulation of receptor-mediated endocytosis (GO:0048260), cytoplasm/cytosol localization. A second, well-supported direct MF is MAP-kinase (ERK) binding (GO:0051019), underlying ERK/Torso/MAPK inhibition.
• Non-core (pleiotropic developmental / immune signalling-attenuation roles, many seen only on over-expression): negative regulation of Toll (×2), Torso, Smoothened (×2), MAPK cascade, Notch; protein destabilization; positive regulation of protein desumoylation; locomotory exploration behavior; sensory perception.
• GO:0005515 protein binding (IPI, PMID:20802461) — two rows from this reference, adjudicated separately. The rolled/ERK row is uninformative → MODIFY to GO:0051019 mitogen-activated protein kinase binding (Krz–ERK/rolled). The Cactus (Q03017) row is well supported experimentally (co-IP from S2 cells plus in vitro translated proteins) but GO has no I-kappaB binding MF to sharpen it to (GO:0051059 NF-kappaB binding names the wrong target, since Cactus is the inhibitor), so no replacement is proposed and it is KEEP_AS_NON_CORE; the biology is already captured by GO:0045751.
• GO:0007165 signal transduction (IEA) is very general but not wrong (arrestin is a signalling regulator) → ACCEPT.
• No REMOVE calls: every experimental annotation is supported by its cited paper; abstract-only Notch (PMID:16284625) is directly supported by its own abstract.

GO IDs verified

• GO:0051019 mitogen-activated protein kinase binding — MF, subclass of protein kinase binding (AmiGO). Used for the protein-binding MODIFY and core_function 2.
• GO:0001664 (GPCR binding, MF), GO:0002031 (GPCR internalization, BP), GO:0048260 (positive regulation of receptor-mediated endocytosis, BP), GO:0043409 (negative regulation of MAPK cascade, BP), GO:0005737 (cytoplasm, CC), GO:0005829 (cytosol, CC) — used in core_functions.