Biology:WWC2

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

WW and C2 domain containing 2 (WWC2) is a protein that in humans is encoded by the WWC2 gene (4q35.1). Though function of WWC2 remains unknown, it has been predicted that WWC2 may play a role in cancer.

Gene

Locus

The human gene WWC2 is found on chromosome 4 at band 4q35.1. The gene is found on the plus strand of the chromosome and is 8,822 base pairs long. The gene contains 23 exons. The WWC2 locus is quite complex and appears to produce several proteins with no sequence overlap[1]


Aliases

A common alias of the gene is BH3-Only Member B (BOMB)[2]

Homology

Paralogs

There are two paralogs of WWC2 found in humans, WWC1 and WWC3. WWC1 is located on chromosome 5 and is a probable regulator of the Hippo signaling pathway that plays a role in tumor suppression by restricting proliferation and promoting apoptosis.[3] WWC3 is located on chromosome X and not much is known about its function.

Sequence Genus/species Accession # Seq. length Seq. identity
WWC2 Homo sapiens NP_079225 1192 aa 100%
KIBRA (WWC1) Homo sapiens AA015881 1113 aa 49.7%
WWC3 Homo sapiens NP_056506 1092 aa 41.2%

Orthologs

WWC2 is highly conserved in Mammalia, Aves, Reptilia, and Amphibia, as well as the rare coelacanth, which is more closely related to lungfish, reptiles, and mammals than ray finned fish. WWC2 is conserved in some Actinopterygii, Gastropoda, and Bivalvia. However, WWC2 is not well conserved in Insecta.

Genus/Species Common name Date of divergence Accession # Seq. identity
Homo sapiens Human N/A NP_079225 100%
Pan troglodytes Chimpanzee 6.1 MYA XP_003310624 99%
Heterocephalus glaber Naked mole rat 91 MYA EHB18748 88%
Mus musculus Mouse 91 MYA NP_598552 86%
Orcinus orca Killer whale 97.4 MYA XP_004281794 90%
Bos mutus Yak 97.4 MYA XP_005903227 84%
Alligator mississippiensis Alligator 324.5 MYA XP_006269678 79.2%
Pelodiscus sinensis Chinese soft-shelled turtle 324.5 MYA XP_006130219 79%
Anas platyrhynchos Mallard 324.5 MYA EOA93642 78%
Falco peregrinus Peregrine falcon 324.5 MYA XP_005230882 77%
Ficedula albicollis Collared flycatcher 324.5 MYA XP_005045160 76%
Xenopus (Silurana) tropicalis Western clawed frog 361.2 MYA NP_001004872 71%
Ophiophagus hannah King cobra 362.2 MYA ETE71408 71%
Latimeria chalumnae Coelacanth 430 MYA XP_005989542 72%
Takifugu rubripes Pufferfish 454.6 MYA XP_003973883 55%
Danio rerio Zebrafish 454.6 MYA XP_689275 53%
Xiphophorus maculatus Southern platyfish 454.6 MYA XP_005800442 51%
Aplysia californica California sea hare (slug) 782.7 MYA XP_005096216 51%
Crassostrea gigas Pacific oyster 910 MYA EKC42771 39%
Anopheles darlingi Mosquito 910 MYA ETN67979 34%
Drosophila melanogaster Fruit fly 910 MYA AAF55090.2 28.9%

Protein

Primary sequence

The gene encodes a protein also called WWC2 which is 1,192 amino acids long. The molecular weight of the protein is 133.9 kilodaltons.[4] The protein is serine rich with no charge clusters, hydrophobic segments or transmembrane domains. The isoelectric point is 5.23800[5]

Domains and motifs

WWC2 is a member of the WWC protein family[6] which consists of a WW domain and a C2 domain. WWC2 contains two WW domains and one C2 domain. WWC2 also contains two domains of unknown function, DUF342 and DUF444. A leucine zipper is located at position 854.

Post translational modifications

The WWC2 protein is predicted to be highly phosphorylated.[7] There are 89 predicted sites of serine phosphorylation, 17 predicted sites of threonine phosphorylation, and 11 predicted sites of tyrosine phosphorylation. These numbers were relatively consistent in orthologous proteins.

It is also predicted that p38 mitogen-activated protein kinases and glycogen synthase kinase 3 bind at position T3, and casein kinase 2 binds at positions S13 and T50.[8]

Expression

Expression

WWC2 is expressed at a low level, and is tissue specific to the uterus, thyroid, lung, and liver. WWC2 expression is found to be elevated in the blastocyst and fetal stages of development.

Transcript variants

Many transcript variants exist for WWC2. Those that change a highly conserved amino acid residue, or surround a highly conserved amino acid residue are listed below:

SNP Allele Protein residue Amino acid position
rs200024780 A to G Tyr (T) to Cys (C) 470
rs191286964 C to T Arg (R) to Cys (C) 1082
rs139606516 G to T Arg (R) to Leu (L) 1082
rs149738870 A to G Asn (N) to Ser (S) 1084

Interacting proteins

Transcription factors

Transcription factors with highest matrix scores that bind to sequences within the promoter (ID GXP_1499160) are shown below:

  • STAT (signal transducer and activator of transcription)
  • Muscle TATA box
  • NOLF (neuron-specific olfactory factor)
  • XCPE (X gene core promoter element 1)
  • CTCF (CCCTC-binding factor)
  • HDBP (Huntington's disease gene regulatory region)
  • OCT1 (octamer binding protein)
  • E2FF (E2F-myc activator cell cycle regulator)
  • ZF57 (KRAB domain zinc finger protein 57)
  • ZF07 (C2H2 zinc finger transcription factor 7)
  • EGRF (EGR/nerve growth factor induced protein)
  • CDEF (cell cycle dependent element - CDF-1 binding site)
  • AP2F (activator protein 2)

Proteins

Potential interacting proteins include: YWHAZ, YWHAQ, RUVBL1, and REPS1.

Clinical significance and Current bioinformation

While the exact function of WWC2 remains unknown, several mutations and variants of WWC2 have been researched in disease. A novel missense mutation in WWC2 was analyzed in Restless Leg Syndrome, but was not identified as a candidate gene.[9] One study examined the role of Drosophila KIBRA (WWC1) in the Expanded-Hippo-Warts signaling cascade, which is involved with tumor suppression. The study stated that copy number aberration, translocation, and point mutations of WWC2, as well as other genes, should be further investigated in human cancers.[10] WWC2 alias, BOMB, was researched in a grant suggesting that BOMB, along with two other genes (APOL6 and APOL1) promoted cell death in p53-null HCT116 cells.

References

  1. AceView. NCBI. WWC2 homo sapiens. https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&term=WWC2&submit=Go
  2. Gene cards. WWC2. Homo sapiens. https://www.genecards.org/cgi-bin/carddisp.pl?gene=WWC2&search=wwc2
  3. Gene Cards. KIBRA. Homo Sapiens. https://www.genecards.org/cgi-bin/carddisp.pl?gene=WWC1
  4. SDSC Workbench. SAPS Program. WWC2. Homo sapiens
  5. SDSC Workbench. PI Program. WWC2. Homo sapiens
  6. "Evolutionary and molecular facts link the WWC protein family to Hippo signaling". Molecular Biology and Evolution 31 (7): 1710–23. 2014. doi:10.1093/molbev/msu115. PMID 24682284. 
  7. ExPASy. NetPhos 2.0 Program. http://www.cbs.dtu.dk/cgi-bin/webface2.fcgi?jobid=5341A6B500000A4BB89D0F8C&wait=20
  8. ExPASy. NetPhosK 1.0 Program. http://www.cbs.dtu.dk/cgi-bin/webface2.fcgi?jobid=5341A89700000A4B44994EF8&wait=20
  9. "Exome sequencing in a family with restless legs syndrome". Movement Disorders 27 (13): 1686–9. November 2012. doi:10.1002/mds.25191. PMID 23192925. 
  10. "Function and cancer genomics of FAT family genes (review)". International Journal of Oncology 41 (6): 1913–8. December 2012. doi:10.3892/ijo.2012.1669. PMID 23076869.