EHD3

Last updated
EH-domain containing 3
Identifiers
SymbolEHD3
Alt. symbolsPAST3
Alt. namesPAST 3

Eps15 homology domain-containing protein 3, abbreviated as EHD3 and also known as PAST3, is a protein encoded by the EHD3 gene. It has been observed in humans, mice and rats. It belongs to the EHD protein family, a group of four membrane remodeling proteins related to the Dynamin superfamily of large GTPases. Although the four of them are 70-80% amino acid identical, they all have different locations. [1] Its main function is related to endocytic transport.

Contents

Taxonomic identifier9606 [NCBI]
Length (aa)535
Molecular mass (kDa)60.887
Molecular weight (g/mol)60,887.13
Charge0.0
Isoelectric point6.5173 [2]
Gene typeProtein coding
Gene location2p23.1
Exon count7
Organism Homo sapiens
OrthologsMice and rats

Structure

Primary structure

The primary structure of a protein is related to which amino acids a protein is made of. EHD3 has 535 amino acids, of which almost three-quarters are common in the four EHD proteins. This protein has a molecular mass of 60887 daltons.

Secondary structure

The secondary structure of the EHD3 protein still remains unknown.

Tertiary structure

The tertiary structure of a protein involves the domains it is formed of. EHD3 protein is formed of four different domains:

Domains of the EHD3 protein. In orange, the EH domain-containing protein N-terminal. In yellow, the dynamin-type G domain. In navy blue, the coiled-coil domain. In green, the ED domain. And in blue, the EF-hand domain. Protein EHD3 domains .tif
Domains of the EHD3 protein. In orange, the EH domain-containing protein N-terminal. In yellow, the dynamin-type G domain. In navy blue, the coiled-coil domain. In green, the ED domain. And in blue, the EF-hand domain.

Post-translational modifications

Protein post-translational modifications (PTM) increase the functional diversity of the proteome by the covalent addition of functional groups or proteins, by the hydrolysis of peptide bonds that link amino acids together or by the degradation of different parts of the protein. [6] The EHD3 protein suffers three kinds of amino acid modifications:

Post-translational modifications of the EHD3. In red, acetylations. In pink, cross-links. And in purple, phosphorylations. Post translational modifications of EHD3.tif
Post-translational modifications of the EHD3. In red, acetylations. In pink, cross-links. And in purple, phosphorylations.

Functions

The EH domain is a common motif in a family of proteins involved in endocytic trafficking. This family of four paralogs (EHD1-EHD4) has been implicated in receptor intracellular trafficking, particularly in internalization and recycling to the plasma membrane. The list of functions of EHD proteins is just starting to be populated. [8]

EHD3 is a moonlighting protein, which means it can perform different functions depending on the tissue where the protein is located. The main functions are the following:

EHD3 can be mainly found in human heart and brain, as well as kidney, ovary and liver. EHD3 Location in Human Body.png
EHD3 can be mainly found in human heart and brain, as well as kidney, ovary and liver.

Gene

The gene that encodes the human EHD3 protein is located in chromosome number 2, most specifically in the 23.1 region. On the other hand, the murine EHD3 gene is located in chromosome 17, in the 21st region. The human gene is formed approximately of 35,438 bases. [16]

Both the human and the mouse genes contain a polymorphic (CA) repeat in their 3'UTR. Specifically, human tissue presents two, 4.2- and 3.6-kb, EHD3 RNA species. While the gene is highly expressed in heart and brain, it is moderately expressed in kidney, ovary, liver and placenta.

Location

EHD3 protein has been found in humans and mice. It can be mainly found in human heart and brain, as well as kidney, ovary and liver.

EHD3 (expressed as a green fluorescent fusion protein) was localized in endocytic vesicles, mostly in recycling vesicles, and in membrane tubules, which implicates the N-terminal domain. Therefore, is not rare that this protein regulates the microtubule-dependent movement.

Pathology

Mutagenesis

EHD3 principal mutations. EHD3 Mutations.tif
EHD3 principal mutations.

Diseases

The lack or malfunction of this protein in the human body can cause some diseases such as heart failure [19] or a depressive disorder. Losing EHD3 is also known to be an early step towards glioma formation.

Major Depressive Disorder (MDD)

Women are more propense to depressive disorders and anxiety than men, although the reason is still unknown. Still, recent studies have shown the direct relation of some genes and their encoded proteins with the disease, including EHD3. Three SNPs have been found in the gene that are concretely linked to MDD and anxious behaviour exclusively in female patients, which suggest a gender differentiating role in MDD. [20]

EHD3 in glioma formation

Since EHD3 is most abundantly expressed in brain tissues, its role in brain cancer progression has been investigated.

EHD3 gene has functions as a tumor suppressor gene and the loss of its expression is a very common event in gliomas. The loss of EHD3 transcripts is observed even in the least advanced grades, I and II, suggesting that EHD3 loss is an early event during gliomagenesis. Moreover, EHD3 has growth inhibitory functions and induces a G0/G1 cell cycle arrest and apoptotic death. It is possible that the proapoptotic role of EHD3 involves functions not related to its role in trafficking, but rather to its ATP/GTP-binding ability and possible impact on protein kinase signaling. [21]

References

  1. "EHD Home Page: An ATPase involved in membrane remodelling". www.endocytosis.org. Archived from the original on 2016-10-29. Retrieved 2016-10-15.
  2. "Help - Homo_sapiens - Ensembl genome browser 106".
  3. EMBL-EBI, InterPro. "EH domain-containing protein, N-terminal (IPR031692) < InterPro < EMBL-EBI". www.ebi.ac.uk. Retrieved 2016-10-15.
  4. EMBL-EBI, InterPro. "Dynamin-type guanine nucleotide-binding (G) domain (IPR030381) < InterPro < EMBL-EBI". www.ebi.ac.uk. Retrieved 2016-10-15.
  5. EMBL-EBI, InterPro. "EH domain (IPR000261) < InterPro < EMBL-EBI". www.ebi.ac.uk. Retrieved 2016-10-15.
  6. "Overview of Post-Translational Modifications (PTMs)". Thermo Fisher.
  7. "Acetylation". www.uniprot.org. Retrieved 2016-10-16.
  8. Chukkapalli S, Amessou M, Dekhil H, Dilly AK, Liu Q, Bandyopadhyay S, Thomas RD, Bejna A, Batist G, Kandouz M (April 2014). "Ehd3, a regulator of vesicular trafficking, is silenced in gliomas and functions as a tumor suppressor by controlling cell cycle arrest and apoptosis". Carcinogenesis. 35 (4): 877–85. doi:10.1093/carcin/bgt399. PMID   24306026.
  9. Galperin E, Benjamin S, Rapaport D, Rotem-Yehudar R, Tolchinsky S, Horowitz M (August 2002). "EHD3: a protein that resides in recycling tubular and vesicular membrane structures and interacts with EHD1". Traffic. 3 (8): 575–89. doi: 10.1034/j.1600-0854.2002.30807.x . PMID   12121420.
  10. Norris PR (1977). "Thermoacidophilic archaebacteria: potential applications". Biochemical Society Symposium. 58 (1): 171–80. PMC   1445405 . PMID   1445405.
  11. "Ehd3 - EH domain-containing protein 3 - Mus musculus (Mouse) - Ehd3 gene & protein". www.uniprot.org. Retrieved 2016-10-21.
  12. Lu Q, Insinna C, Ott C, Stauffer J, Pintado PA, Rahajeng J, Baxa U, Walia V, Cuenca A, Hwang YS, Daar IO, Lopes S, Lippincott-Schwartz J, Jackson PK, Caplan S, Westlake CJ (March 2015). "Early steps in primary cilium assembly require EHD1/EHD3-dependent ciliary vesicle formation". Nature Cell Biology. 17 (3): 228–240. doi:10.1038/ncb3109. PMC   4344897 . PMID   25686250.
  13. Galperin E, Benjamin S, Rapaport D, Rotem-Yehudar R, Tolchinsky S, Horowitz M (August 2002). "EHD3: a protein that resides in recycling tubular and vesicular membrane structures and interacts with EHD1". Traffic. 3 (8): 575–89. doi: 10.1034/j.1600-0854.2002.30807.x . PMID   12121420.
  14. Kotowski SJ, Hopf FW, Seif T, Bonci A, von Zastrow M (July 2011). "Endocytosis promotes rapid dopaminergic signaling". Neuron. 71 (2): 278–90. doi:10.1016/j.neuron.2011.05.036. PMC   3417347 . PMID   21791287.
  15. "Tissue expression of EHD3 - Summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2016-10-21.
  16. "EHD3". www.genecards.org. Retrieved 2016-10-17.
  17. "RAB11FIP2 - Rab11 family-interacting protein 2 - Homo sapiens (Human) - RAB11FIP2 gene & protein". www.uniprot.org. Retrieved 2016-10-22.
  18. "EHD3 - EH domain-containing protein 3 - Homo sapiens (Human) - EHD3 gene & protein". www.uniprot.org. Retrieved 2016-10-22.
  19. Gudmundsson H, Curran J, Kashef F, Snyder JS, Smith SA, Vargas-Pinto P, Bonilla IM, Weiss RM, Anderson ME, Binkley P, Felder RB, Carnes CA, Band H, Hund TJ, Mohler PJ (May 2012). "Differential regulation of EHD3 in human and mammalian heart failure". Journal of Molecular and Cellular Cardiology. 52 (5): 1183–90. doi:10.1016/j.yjmcc.2012.02.008. PMC   3360944 . PMID   22406195.
  20. Wang L, Shi C, Zhang K, Xu Q (May 2014). "The gender-specific association of EHD3 polymorphisms with major depressive disorder". Neuroscience Letters. 567: 11–4. doi:10.1016/j.neulet.2014.02.055. PMID   24607927. S2CID   28116425.
  21. Chukkapalli S, Amessou M, Dekhil H, Dilly AK, Liu Q, Bandyopadhyay S, Thomas RD, Bejna A, Batist G, Kandouz M (April 2014). "Ehd3, a regulator of vesicular trafficking, is silenced in gliomas and functions as a tumor suppressor by controlling cell cycle arrest and apoptosis". Carcinogenesis. 35 (4): 877–85. doi:10.1093/carcin/bgt399. PMID   24306026.