Q95T12 · FLOWR_DROME

Function

function

Transmembrane protein which mediates synaptic endocytosis, fitness-based cell culling, neuronal culling, morphogen gradient scaling, and calcium transport (PubMed:20627080, PubMed:23810538, PubMed:25601460, PubMed:28011160, PubMed:33300871, PubMed:35301437).
Regulates synaptic endocytosis and hence couples exo- with endocytosis (PubMed:19737521, PubMed:28414717, PubMed:29288152, PubMed:33300871).
Controls two major modes of synaptic vesicle (SV) endocytosis in the synaptic boutons of neuromuscular junctions (NMJs); Ca2+ channel-independent Clathrin-mediated endocytosis (CME) in response to mild stimulation, and Ca2+ channel-dependent activity-dependent bulk endocytosis (ADBE) in response to strong stimulation (PubMed:28414717, PubMed:33300871).
Functions in ADBE and subsequent SV reformation from bulk endosomes by initiating Ca2+ channel-dependent phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) compartmentalization in synaptic boutons (PubMed:28414717, PubMed:33300871).
There it acts at the periactive zone to provide the low Ca2+ levels required to initiate Calcineurin activation and upregulate PtdIns(4,5)P2 (PubMed:33300871).
Conversely PtdIns(4,5)P2 enhances fwe Ca2+ channel-activity, establishing a positive feedback loop that induces PtdIns(4,5)P2 microdomain at the periactive zone (PubMed:33300871).
These microdomains trigger bulk membrane invagination (i.e. ADBE) by triggering actin polymerization while also promoting localization of fwe to bulk endosomes, thereby removing the ADBE trigger to reduce endocytosis and prevent excess membrane uptake (PubMed:33300871).
PtdIns(4,5)P2 then promotes SV reformation from the bulk endosomes, to coordinate ADBE and subsequent SV reformation (PubMed:33300871).
Different combinations of the flower isoforms at the cell membrane are also required for the identification and elimination of suboptimal or supernumerary cells during development, regeneration, and adulthood (PubMed:20627080, PubMed:20951347, PubMed:23810538, PubMed:25601460, PubMed:28011160, PubMed:30590040).
Required for the recognition and elimination of unfit cells in the developing wing during cell competition (PubMed:20627080).
Also required for efficient identification and elimination of injured, damaged and/or dysfunctional neurons during regeneration of the adult brain (PubMed:25754635, PubMed:30590040).
In the developing pupal retina, mediates the elimination of unwanted postmitotic neurons, including supernumerary photoreceptor neurons that form at the periphery of the retina and are contained within incomplete ommatidia units (PubMed:23810538).
Downstream of the flower fitness fingerprints, cells identified as unwanted or unfit are eliminated via apoptosis through the expression of ahuizotl (azot) (PubMed:25601460, PubMed:30590040).
However, the cells marked for elimination by the flower isoforms only undergo apoptosis if additional thresholds are met; 1 their neighboring fit/healthy cells express different levels of the fwe isoforms, and 2 the levels of the protective signal SPARC expressed by the loser or unwanted cells are unable to inhibit caspase activation (PubMed:20627080, PubMed:20951347, PubMed:23810538).
These additional thresholds for flower-mediated apoptosis, allows useful cells to recover from transient and limited stress before they are unnecessarily eliminated (PubMed:20951347).
Functions with dally and magu in a mechanism of scaling, which utilises apoptosis to ensure that the dpp morphogen gradient, which mediates organ growth, remains proportional to the size of the growing wing (PubMed:35301437).
In this mechanism, fwe represses dally- and Magu-dependent activity in expanding the gradient, and dally/Magu inhibits fwe-dependent apoptosis to keep cell death rate low (PubMed:35301437).
When the levels of these different proteins are optimally regulated the gradient correctly scales with organ growth but when this fails, fwe-mediated apoptosis is activated to trim the developing tissue to match the correct size of the gradient (PubMed:35301437).

Isoform Ubi

Functions with the other flower isoforms to produce tissue-specific fitness fingerprints that identify unfit or fit cells during cell selection processes in order to maintain tissue health (PubMed:20627080, PubMed:25601460).
In the wing imaginal disk, this isoform is highly expressed in healthy/normal cells but is down-regulated in cells with decreased fitness (PubMed:20627080).
During cell competition, if levels of this isoform in unfit cells is lower than in the surrounding neighboring cells, the suboptimal cells are recognized as 'loser' cells, and undergo elimination via apoptosis to be replaced by the surrounding healthy 'winner' cell population (PubMed:20627080).

Isoform Lose-A

Functions with the other flower isoforms to produce tissue-specific fitness fingerprints that identify unfit or fit cells during cell selection processes in order to maintain tissue health (PubMed:20627080, PubMed:25601460).
In the wing imaginal disk, this isoform displays low levels of expression in healthy/normal cells but is up-regulated in cells with decreased fitness (PubMed:20627080, PubMed:25601460).
During cell competition, if levels of this isoform in unfit cells is higher than in the surrounding neighboring cells, the suboptimal cells are recognized as 'loser' cells, and undergo elimination via apoptosis to be replaced by the surrounding healthy 'winner' cell population (PubMed:20627080, PubMed:25601460).

Isoform Lose-B

Functions with the other flower isoforms to produce tissue-specific fitness fingerprints that identify unfit cells for cell selection processes during development, regeneration, and to maintain tissue health (PubMed:20627080, PubMed:25601460, PubMed:25754635, PubMed:30590040).
During cell competition in certain tissues, marks suboptimal or damaged cells as 'loser' cells (PubMed:20627080, PubMed:25601460, PubMed:25754635, PubMed:30590040).
In cells of the wing imaginal disk and damaged or dysfunctional neurons in the adult optic lobe, this isoform displays low to no expression in healthy/normal cells but is up-regulated in cells with decreased fitness or damage-affected neurons (PubMed:20627080, PubMed:25754635, PubMed:30590040).
During cell competition, if levels of this isoform in unfit cells is higher than in the surrounding neighboring cells, the suboptimal cells are recognized as 'loser' cells, and undergo elimination via apoptosis to be replaced by the surrounding healthy/undamaged 'winner' cell population (PubMed:20627080, PubMed:25754635, PubMed:30590040).
In the developing pupal retina, also required for the recognition and elimination of postmitotic neurons, including supernumerary photoreceptor neurons that form at the periphery of the retina and are contained within incomplete ommatidia units (PubMed:23810538).
Activity at the peripheral retina is induced by the wg signaling pathway but, once activated, it promotes apoptosis of supernumerary photoreceptor neurons independently of wg signaling and snail function (PubMed:23810538).

Miscellaneous

The name 'flower' derives from mutants that display numerous extra boutons that are small, clustered, and flowery in nature.

Activity regulation

Channel activity is inhibited by La3+, which reduces Ca2+ influx and thus inhibits it's function in promoting activity-dependent bulk endocytosis (ADBE) in response to high stimuli.

Features

Showing features for site.

TypeIDPosition(s)Description
Site79Calcium ion selectivity

GO annotations

AspectTerm
Cellular Componentcell projection
Cellular Componentendosome
Cellular Componentplasma membrane
Cellular Componentpresynaptic membrane
Cellular Componentsynaptic vesicle membrane
Molecular Functioncalcium channel activity
Molecular Functionidentical protein binding
Biological Processbulk synaptic vesicle endocytosis
Biological Processcalcium ion transmembrane transport
Biological Processcalcium ion transport
Biological Processcell competition in a multicellular organism
Biological Processclathrin-dependent synaptic vesicle endocytosis
Biological Processphotoreceptor cell differentiation
Biological Processpositive regulation of neuron apoptotic process
Biological Processpositive regulation of presynaptic cytosolic calcium concentration
Biological Processregulation of apoptotic process
Biological Processsynaptic vesicle endocytosis
Biological Processvesicle-mediated transport

Keywords

Protein family/group databases

    • 1.A.55.1.2the synaptic vesicle-associated ca2+ channel, flower (flower) family

Names & Taxonomy

Protein names

  • Recommended name
    Calcium channel flower
  • Short names
    3L5

Gene names

    • Name
      fwe
    • Synonyms
      flower
    • ORF names
      CG6151

Organism names

  • Taxonomic identifier
  • Strain
    • Berkeley
  • Taxonomic lineage
    Eukaryota > Metazoa > Ecdysozoa > Arthropoda > Hexapoda > Insecta > Pterygota > Neoptera > Endopterygota > Diptera > Brachycera > Muscomorpha > Ephydroidea > Drosophilidae > Drosophila > Sophophora

Accessions

  • Primary accession
    Q95T12
  • Secondary accessions
    • Q8IQM8
    • Q9VUU2

Proteomes

Organism-specific databases

Subcellular Location

Cell membrane
; Multi-pass membrane protein
Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane
; Multi-pass membrane protein
Endosome
Note: Upon fusion of the synaptic vesicle (SV) with the presynaptic membrane, protein transfers from the SV to the periactive zones where endocytosis is known to occur (PubMed:19737521, PubMed:28414717, PubMed:33300871).
Upon high K+ stimulation, expression levels in NMJ boutons are higher in bulk endosomes than in synaptic vesicles, suggesting that it is recycled to bulk endosomes after it activates ADBE (PubMed:33300871).

Isoform Ubi

Cell membrane
; Multi-pass membrane protein
Note: Localizes to the apico-lateral membranes in wing imaginal disks and salivary gland cells.

Isoform Lose-A

Cell membrane
; Multi-pass membrane protein

Isoform Lose-B

Cell membrane
; Multi-pass membrane protein

Features

Showing features for topological domain, transmembrane.

TypeIDPosition(s)Description
Topological domain1-34Cytoplasmic
Transmembrane35-55Helical
Topological domain56-65Extracellular
Transmembrane66-88Helical
Topological domain89-106Cytoplasmic
Transmembrane107-127Helical
Topological domain128-194Extracellular

Keywords

Phenotypes & Variants

Disruption phenotype

Lethal; mutants die either during the embryonic stage or the first instar larval stage (PubMed:28011160).
Embryos frequently display head involution defects, some do not develop a cuticle and/or occasionally display dorsal closure defects (PubMed:28011160).
The nervous system of embryos also displays developmental defects (PubMed:19737521, PubMed:20627080).
In presynaptic terminals, intracellular resting calcium levels and endocytosis is impaired, whereas exocytosis is normal (PubMed:19737521).
Boutons at the neuromuscular junctions exhibit a significant depletion in the number of synaptic vesicles (PubMed:19737521).
There are numerous extra boutons which are often small, clustered, and flowery in nature (PubMed:19737521).
Mutant nerve terminals display omega structures and collared pits (PubMed:19737521).
RNAi-mediated knockdown in wing disks reduces cell apoptosis during Myc-mediated cell competition experiments (PubMed:28011160, PubMed:35301437).
RNAi-mediated knockdown in the posterior compartment of the wing disk, has no effect on tissue growth under normal conditions however, growth is reduced in tissues undergoing Myc-mediated cell competition (PubMed:20627080).
RNAi-mediated knockdown during Myc-mediated cell competition experiments, has no effect on up-regulation of SPARC in loser cells (PubMed:20951347).

Isoform Ubi

RNAi-mediated knockdown in the posterior compartment of the wing disk, does not induce apoptosis and has no effect on compartment growth.

Features

Showing features for mutagenesis.

TypeIDPosition(s)Description
Mutagenesis29-33In isoform Q95T12-2; Following high K+ stimulation, displays reduced formation of PtdIns(4,5)P2 microdomains at periactive zones and an impaired Ca2+ response in NMJ boutons, and decreased binding to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). Unable to rescue stimulation induced activity-dependent bulk endocytosis (ADBE) and synaptic vesicle replacement in mutants. No affect on localization to the presynaptic compartments of NMJ boutons. Severe decrease in binding to PtdIns(4,5)P2; when associated with A-95, A-100, A-105 and 146-A--A-150.
Mutagenesis79Impaired Ca2+ channel activity. Heterologous expression in salivary glands shows inhibition of calcium influx. Following strong stimulation that induces activity-dependent bulk endocytosis (ADBE), loses ability to promote the Ca2+ channel-dependent formation of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) microdomains at periactive zones in the synaptic boutons of larval NMJs. However, no effect on activating Clathrin-mediated endocytosis (CME) in NMJ boutons in response to mild stimulation.
Mutagenesis95In isoform Q95T12-2; Decreased binding to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2); when associated with A-100, A-105 and 146-A--A-150. Severe decrease in binding to PtdIns(4,5)P2; when associated with 29-A--A-33, A-100, A-105 and 146-A--A-150.
Mutagenesis100In isoform Q95T12-2; Decreased binding to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2); when associated with A-95, A-105 and 146-A--A-150. Severe decrease in binding to PtdIns(4,5)P2; when associated with 29-A--A-33, A-95, A-105 and 146-A--A-150.
Mutagenesis105In isoform Q95T12-2; Decreased binding to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2); when associated with A-95, A-100 and 146-A--A-150. Severe decrease in binding to PtdIns(4,5)P2; when associated with 29-A--A-33, A-95, A-100 and 146-A--A-150.
Mutagenesis128In allele DB25; defect in synaptic transmission and homozygous lethal.
Mutagenesis146-150In isoform Q95T12-2; Following high K+ stimuli, no effect on synaptic vesicle localization, regulation of presynaptic Ca2+ concentration, induction of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) in NMJ boutons or activity-dependent bulk endocytosis (ADBE). Severe decrease in binding to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2); when associated with 29-A--A-33, A-95, A-100 and A-105.

PTM/Processing

Features

Showing features for chain.

TypeIDPosition(s)Description
ChainPRO_00003892341-194Calcium channel flower

Proteomic databases

PTM databases

Expression

Tissue specificity

Detected in the imaginal wing disk (at protein level).

Isoform Ubi

Detected throughout the adult brain, including the optic lobe but, at much lower levels of expression than isoform Lose-A.

Isoform Lose-A

Detected in the optic lobe (at protein level) (PubMed:25754635).
Detected throughout the adult brain, including the optic lobe (PubMed:25754635, PubMed:30590040).
Expressed in damaged and undamaged optic lobe neurons (PubMed:25754635, PubMed:30590040).

Isoform Lose-B

Expressed in optic lobe neurons, with higher levels of expression in suboptimal neurons (PubMed:30590040).
Specifically expressed in injury-damaged optic lobe neurons (PubMed:25754635).

Induction

Isoform Lose-A

Induced in the midgut and adult brain by tissue damage caused by UV irradiation.

Isoform Lose-B

Induced in the midgut and adult brain by tissue damage caused by UV irradiation (PubMed:25601460).
Up-regulated in optic lobe neurons that have been damaged by lesioning the optic lobe unilaterally causing penetrating traumatic brain injury (PubMed:25754635).

Developmental stage

Isoform Ubi

Detected in all imaginal disk cells and salivary gland cells (at protein level) (PubMed:20627080).
In pupae, ubiquitously expressed in the retina including the neuronal layer (at protein level) (PubMed:23810538).

Isoform Lose-A

In pupal retinas, detected at 24 hr after pupal formation (APF) to 42 hr APF, where it is ubiquitously expressed throughout the retina including the neuronal layer (at protein level) (PubMed:23810538).
Expressed in the neuropils of embryonic, larval, adult CNS, and R1-R6 terminals. Expression in the central nervous system (CNS) starts at embryonic stage 13 (PubMed:19737521).

Isoform Lose-B

In pupal retinas, specifically expressed at the periphery in photoreceptor neurons that are undergoing apoptosis (at protein level) (PubMed:23810538).
Expression in the pupal retinas is not detected until 36 hr after pupal formation (APF) and is maintained until 44 hr APF; this is during the retina 'late cell death' event when peripheral ommatidia are being eliminated from the final structure (at protein level) (PubMed:23810538).

Gene expression databases

Interaction

Subunit

Isoform Ubi

Associates with the dally/ magu complex.

Isoform Lose-A

Homomultimer (PubMed:19737521).
Associates with the dally/ magu complex (PubMed:35301437).

Isoform Lose-B

Associates with the dally/ magu complex.

Binary interactions

TypeEntry 1Entry 2Number of experimentsIntact
BINARY Q95T12fwe Q95T127EBI-169467, EBI-169467
BINARY Q95T12-2fwe Q95T12-25EBI-2497181, EBI-2497181

Protein-protein interaction databases

Family & Domains

Features

Showing features for region.

TypeIDPosition(s)Description
Region135-157In isoform Q95T12-3; Important for promoting apoptosis
Region135-192In isoform Q95T12-2; Important for promoting apoptosis

Sequence similarities

Belongs to the calcium channel flower family.

Keywords

Phylogenomic databases

Family and domain databases

Sequence & Isoforms

Align isoforms (3)
  • Sequence status
    Complete

This entry describes 3 isoforms produced by Alternative splicing.

Q95T12-1

This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

  • Name
    Ubi
  • Synonyms
    A
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Length
    194
  • Mass (Da)
    20,620
  • Last updated
    2001-12-01 v1
  • Checksum
    2D2817158AD73A57
MSFAEKITGLLARPNQQDPIGPEQPWYLKYGSRLLGIVAAFFAILFGLWNVFSIITLSVSCLVAGILQMVAGFVVMLLEAPCCFVCFGQVNEIAEKVESKPLYFRAGLYIAMAIPPIILCFGLASLFGSGLIFGTGVVYGMMALGKKASAEDMRAAAQQTFGGNTPAQTNDRAGIVNNAQPFSFTGAVGTDSNV

Q95T12-2

  • Name
    Lose-A
  • Synonyms
    LoseA
    , B
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Differences from canonical
    • 150-194: AEDMRAAAQQTFGGNTPAQTNDRAGIVNNAQPFSFTGAVGTDSNV → REDMAAAATSPTQMAGSQAGGQMQMGGDQHITLMEDPDVWRPT

Q95T12-3

  • Name
    Lose-B
  • Synonyms
    LoseB
    , C
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Differences from canonical
    • 147-194: KASAEDMRAAAQQTFGGNTPAQTNDRAGIVNNAQPFSFTGAVGTDSNV → NKHIFLVRNYI

Features

Showing features for alternative sequence.

TypeIDPosition(s)Description
Alternative sequenceVSP_053165147-194in isoform Lose-B
Alternative sequenceVSP_053166150-194in isoform Lose-A

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
AE014296
EMBL· GenBank· DDBJ
AAF49581.1
EMBL· GenBank· DDBJ
Genomic DNA
AE014296
EMBL· GenBank· DDBJ
AAN11767.1
EMBL· GenBank· DDBJ
Genomic DNA
AE014296
EMBL· GenBank· DDBJ
AAN11768.1
EMBL· GenBank· DDBJ
Genomic DNA
AY060385
EMBL· GenBank· DDBJ
AAL25424.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

Disclaimer

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