DENN/MADD domain containing 2C (DENND2C) is a protein that in humans is encoded by the DENND2C gene.[5]

DENND2C
Identifiers
AliasesDENND2C, dJ1156J9.1, DENN domain containing 2C
External IDsMGI: 3036254; HomoloGene: 19542; GeneCards: DENND2C; OMA:DENND2C - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_198459
NM_001256404

NM_177857
NM_001356383
NM_001384113

RefSeq (protein)

NP_001243333
NP_940861

NP_808525
NP_001343312

Location (UCSC)Chr 1: 114.58 – 114.67 MbChr 3: 103.01 – 103.08 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gene

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DENND2C is located on human chromosome 1 at 1p13.2 on the minus strand. The gene spans about 87,200 nucleotides.[6] and has 21 exons.

mRNA

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The main DENND2C mRNA isoform is 6177 nucleotides long. There are three isoforms.[5][8]

Protein

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Protein isoform 1, the longest variant, is 928 amino acids long with a predicted weight of 106.9 kDa.[8] It is alanine-poor relative to other proteins. The theoretical isoelectric point is 8.8. The protein is found in the nucleoplasm.

Structure

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The three-dimensional structure of DENND2C contains a central beta sheet flanked by alpha-helices.[8] Details about its quaternary structure are currently unavailable.

 
Human DENND2C 3D structure. A known phosphorylation site is highlighted in yellow. The uDENN domain is in cyan. The DENN domain is in hot pink. The dDENN is in green.

Clinical significance

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DENND2C’s importance in cancer is highlighted by its regulation by the tumor suppressor p53.[9] As a guanine nucleotide exchange factor for Rab (G-protein), DENND2C plays a key role in intracellular trafficking and cellular signaling. p53 helps maintain cellular balance and prevent cancer by regulating various pathways. Since DENND2C is part of the p53-regulated network, it is predicted to be involved in cancer suppression.

Disruptions in DENND2C's function or its interaction with p53 can interfere with these pathways and contribute to tumor progression. DENND2C’s role in p53-regulated pathways can be used for developing targeted cancer therapies and identifying new biomarkers for cancer diagnosis and prognosis.

Evolutional history

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Orthologs

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DENND2C has orthologs in most vertebrates: mammals, birds, reptiles, amphibians, and fish.[10] This broad conservation highlights its significant role in vertebrates.

Genus/Species Common Name Taxonomic Group Med. Date of Divergence (MYA) Accession Number Sequence Length (aa) Sequence Identity (%)
Mammalia Homo sapiens Human Primates 0 NP_001243333.1 928 100
Mus musculus House mouse Rodentia 87 XP_006501667.1 920 83.1
Orcinus orca Killer whale Artiodactyla 94 XP_049566111.1 935 89.6
Phascolarctos cinereus Koala Diprotodontia 160 XP_020857927.1 938 81.2
Reptilia Chelonia mydas Green sea turtle Testudines 319 XP_027677849.2 938 72.5
Podarcis muralis Common wall lizard Squamata 319 XP_028590394.1 927 69.9
Python bivittatus Burmese python Squamata 319 XP_007429931.1 928 69.4
Alligator mississippiensis American alligator Crocodilia 319 XP_059573447.1 946 67.9
Aves Aptenodytes forsteri Emperor penguin Sphenisciformes 319 XP_009270985.1 932 67.5
Gallus gallus Chicken Galliformes 319 XP_046788775.1 988 66.7
Tyto alba Common barn owl Strigiformes 319 XP_032843159.2 1018 65.8
Chroicocephalus ridibundus Black-headed gull Charadriiformes 319 XP_063212431.1 987 65.7
Amphibia Microcaecilia unicolor Microcaecilia unicolor Gymnophiona 352 XP_030076672.1 941 65.4
Hyla sarda Sardinian tree frog Anura 352 XP_056414351.1 944 63.1
Actinistia Latimeria chalumnae West Indian Ocean coelacanth Coelacanthiformes 415 XP_064425280.1 959 58
Actinopterygii Erpetoichthys calabaricus Reedfish Polypteriformes 429 XP_028652273.2 908 50.4
Lepisosteus oculatus Spotted gar Lepisosteiformes 429 XP_015197870.1 904 49.9
Amphiprion ocellaris Clown anemonefish Perciformes 429 XP_023154128.2 936 47.3
Phycodurus eques Leafy seadragon Syngnathiformes 429 XP_061527912.1 912 45.9
Amblyraja radiata Thorny skate Rajiformes 462 XP_032898655.1 1045 53
 
DENND2C unrooted phylo tree

DENND2C has no known orthologs in invertebrates, bacteria, archaea, protists, plants, fungi and trichoplax. DENND2C probably evolved in more advanced multicellular organisms and is important for their specific biological functions - instead of simpler life forms like the organisms listed above.

Parlaogs

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DENND2A, DENND2B, and DENND2D are closely related paralogs of DENND2C.[11]

Protein Accession Number Sequence Identity (%) Sequence Similarity (%)
DENND2C NP_001243333.1 100 100
DENND2A NP_056504.3 43.4 57.7
DENND2B NP_001363424.1 38.1 50.6
DENND2D NP_079177.2 22.9 32.6

Rate of Evolution

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The protein DENND2C evolves at half the rate of fibrinogen alpha and slightly faster than cytochrome C, indicating that DENND2C has a moderately slow rate of evolution.

Cytochrome c stays similar over time (highly conserved), but fibrinogen alpha changes a lot (less conserved). The graph supports the idea that genetic changes happen steadily over time (linear), as predicted by the molecular clock hypothesis.

 
Corrected Sequence Divergence VS Median Date of Divergence of DENND2C, Cytochrome C and Fibrinogen Alpha for humans, house mouse, green sea turtle, chicken, and clown anemonefish.

Conceptual human translation

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Raw Human DENND2C Conceptual Translation

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000175984Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000007379Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "DENND2C DENN domain containing 2C [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2024-06-10.
  6. ^ "AceView: Gene:AMPD1andDENND2CandBCAS2, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView". www.ncbi.nlm.nih.gov. Retrieved 2024-06-10.
  7. ^ Marat AL, Dokainish H, McPherson PS (April 2011). "DENN domain proteins: regulators of Rab GTPases". The Journal of Biological Chemistry. 286 (16): 13791–13800. doi:10.1074/jbc.R110.217067. PMC 3077579. PMID 21330364.
  8. ^ a b c "DENN domain-containing protein 2C". AlphaFold Protein Structure Database. Q68D51. Retrieved 2024-06-10 – via EMBL-EBI.
  9. ^ Bieging-Rolett KT, Kaiser AM, Morgens DW, Boutelle AM, Seoane JA, Van Nostrand EL, et al. (November 2020). "Zmat3 Is a Key Splicing Regulator in the p53 Tumor Suppression Program". Molecular Cell. 80 (3): 452–469.e9. doi:10.1016/j.molcel.2020.10.022. PMC 7654708. PMID 33157015.
  10. ^ "DENND2C orthologs". NCBI. Retrieved 2024-06-10.
  11. ^ "Gene: DENND2C (ENSG00000175984) - Paralogues - Homo_sapiens - Ensembl genome browser 112". useast.ensembl.org. Retrieved 2024-07-29.