Rabconnectin-3A (''Rbcn-3A'') or DmX (''Drosophila melanogaster'' X-gene) is a gene located on the X chromosome in ''
Drosophila
''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...
'' and encodes for the relatively large
WD-repeat
The WD40 repeat (also known as the WD or beta-transducin repeat) is a short structural motif of approximately 40 amino acids, often terminating in a tryptophan-aspartic acid (W-D) dipeptide. Tandem copies of these repeats typically fold togethe ...
protein, rabconnectin-3A.
[Kraemer, Christiane; Weil, Bernd; Christmann, Markus; Schmidt, Erwin R. (1998-08-31)]
"The new gene DmX from Drosophila melanogaster encodes a novel WD-repeat protein"
''Gene'' 216 (2): 267-276. https://doi.org/10.1016/S0378-1119(98)00347-3 Rabconnectin-3A is involved in
Notch signalling by regulating the vacuolar proton pump
V-ATPase
Vacuolar-type ATPase (V-ATPase) is a highly conserved evolutionarily ancient enzyme with remarkably diverse functions in eukaryotic organisms. V-ATPases acidify a wide array of intracellular organelles and pump protons across the plasma ...
.
''DmX'' is a highly conserved gene and is widely found in insects and mammals.
Two
orthologs
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...
of ''DmX'' exist in humans, ''
DMXL1''
and ''
DMXL2
Dmx-like 2 is a protein that in humans is encoded by the DMXL2 gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to p ...
'', the latter of which codes for the synaptic protein rabconnectin-3α.
Its name comes from the fact that it binds the Ras-related protein Rab3 (human
RAB3A
Ras-related protein Rab-3A is a protein that in humans is encoded by the ''RAB3A'' gene. It is involved in calcium-triggered exocytosis in neurons.
Interactions
RAB3A has been shown to interact with:
* RIMS1,
*UNC13A
Unc-13 homolog A ('' ...
).
Discovery
The discovery of ''DmX'' was published in the journal ''Gene'' in 1998. It was discovered using a
comparative genomics
Comparative genomics is a branch of biological research that examines genome sequences across a spectrum of species, spanning from humans and mice to a diverse array of organisms from bacteria to chimpanzees. This large-scale holistic approach c ...
approach that found sequence homology to ''CpY'', a gene found in the sex determining region of the Y chromosome of the hoverfly ''
C. piger.''
Gene
''DmX'' is located in region 5D5/6-E1 of the X chromosome in ''Drosophila''. The gene is approximately 16 kb long. It includes 15 exons which make up a transcript with a length of 11.5 kb. ''DmX'' has a relatively small promoter region that is likely shorter than 200 bp, leaving little space for regulatory elements. It was suggested that regulatory elements may be present within the first intron which is unusually large at more than 2.4 kb long.
Expression
The transcript for ''DmX'' was found in ''Drosophila'' embryos, larvae, and adults in both males and females, indicating that the gene is expressed in all developmental stages of ''Drosophila'' and does not have sex-specific expression.
Although ''DmX'' was discovered as a homologue for ''CpY'', a gene involved in sex-determination, it does not appear to play a role in sex-determination in ''Drosophila'', as indicated by its non-sex-specific expression.
Protein
''DmX'' encodes for the relatively large protein rabconnectin-3A, which consists of 3427 amino acids and has a molecular weight of approximately 380 kDa. Rabconnectin-3A belongs to the superfamily of WD-repeat proteins which consists of mainly regulatory proteins involved in a variety of cellular processes.
All WD-repeat proteins contain a moderately conserved
WD-repeat motif that consists of approximately 40 amino acids ending with a tryptophan-aspartate (WD) dipeptide. The motif is likely responsible for protein-protein interactions. In most WD-repeat proteins the motif is repeated four to eight times. ''DmX'' has an unusually high repetition of the WD-repeat motif at approximately 30 repeats. It has been suggested that ''DmX'' may be a member of a novel class of WD-repeat proteins which contain significantly more motif repeats.
Role in Notch Signalling
Rabconnectin-3A forms a stable complex with rabconnectin-3B. The rabconnectin-3 complex is involved in regulating Notch signalling, although its exact function is unclear.
Notch signalling is an important pathway involved in cell-cell communication. The pathway regulates the proliferation, differentiation, and death of cells. Signals are transduced by the cell-surface receptor Notch. During Notch synthesis there are three independent cleavage events. The third cleavage event in Notch synthesis is carried out by γ-secretase. This process requires the proton pump V-ATPase which is regulated by the rabconnectin-3 complex.
When Rbcn-3A or Rbcn-3B are absent, Notch synthesis is disrupted between the second and third cleavage events, and Notch is subsequently prevented from entering the nucleus.
Orthologs
Orthologs of ''DmX'' exist in a wide variety of species including ''
C. elegans
''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' ( ...
'', yeast, mice, and humans.
In
zebrafish
The zebrafish (''Danio rerio'') is a species of freshwater ray-finned fish belonging to the family Danionidae of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (an ...
, rabconnectin-3a is involved in
neural crest
The neural crest is a ridge-like structure that is formed transiently between the epidermal ectoderm and neural plate during vertebrate development. Neural crest cells originate from this structure through the epithelial-mesenchymal transition, ...
migration by playing a role in endosomal maturation in neural crest cells. The ''DmX'' ortholog in yeast is ''RAV1''. Rav1 is one of three subunits which make up the RAVE complex which is involved in V-ATPase assembly.
Human
Two orthologs for the ''DmX'' gene have been discovered in humans, ''DMXL1'' and ''
DMXL2
Dmx-like 2 is a protein that in humans is encoded by the DMXL2 gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to p ...
''. The
duplication event that resulted in the two homologues likely occurred in early vertebrates.
''DMXL1''
''DMXL1'' is located on chromosome 5 and codes for a large WD-repeat protein consisting of 3027 amino acids and approximately 28 WD-repeat units. It is expressed in a number of different tissues. Its function is unknown.
In a paper published in 2011, mutations occurring in ''DMXL1'' were linked to tumour growth.
''DMXL2''
''DMXL2'' is located on chromosome 15 and encodes the synaptic protein rabconnectin-3α.
''DMXL2'' plays a role in puberty
and is a regulator of Notch signalling.
Haploinsufficiency of ''DMXL2'' causes delayed puberty, reduced fertility, and abnormal glucose metabolism.
A study published in 2015 identified ''DMXL2'' as a biomarker for ERα positive breast cancer.
''DMXL2'' has also been linked to hearing loss, suggesting that it is involved in inner ear functioning.
[{{cite journal , vauthors = Chen DY, Liu XF, Lin XJ, Zhang D, Chai YC, Yu DH, Sun CL, Wang XL, Zhu WD, Chen Y, Sun LH, Wang XW, Shi FX, Huang ZW, Yang T, Wu H , display-authors = 6 , title = A dominant variant in DMXL2 is linked to nonsyndromic hearing loss , language = En , journal = Genetics in Medicine , volume = 19 , issue = 5 , pages = 553–558 , date = May 2017 , pmid = 27657680 , doi = 10.1038/gim.2016.142 , doi-access = free ]
References
Drosophila melanogaster genes