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EHD3

From Wikipedia, the free encyclopedia
EH-domain containing 3
Identifiers
SymbolEHD3
Alt. symbolsPAST3
Alt. namesPAST 3

Eps15 homology domain-containing protein 3,abbreviated asEHD3and also known asPAST3,is a protein encoded by the EHD3 gene. It has been observed in humans, mice and rats. It belongs to theEHD 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 acididentical, they all have different locations.[1]Its main function is related to endocytic transport.

Taxonomic identifier 9606 [NCBI]
Length (aa) 535
Molecular mass (kDa) 60.887
Molecular weight (g/mol) 60,887.13
Charge 0.0
Isoelectric point 6.5173[2]
Gene type Protein coding
Gene location 2p23.1
Exon count 7
Organism Homo sapiens
Orthologs Mice and rats

Structure

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Primary structure

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Theprimary structureof 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 amolecular massof 60887 daltons.

Secondary structure

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Thesecondary structureof the EHD3 protein still remains unknown.

Tertiary structure

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Thetertiary structureof a protein involves thedomainsit is formed of. EHD3 protein is formed of four different domains:

  • EH domain-containing protein N-terminal,between the 24th and 56th amino acid. This is a short domain that can be found at the beginning of a protein, also known asN-terminus,of manydynaminsand EF-hand domain-containing proteins.[3]
  • Dynamin-type guanine nucleotide-binding (G) domain,between the 56th and 286th amino acid. It consists of a central eight-strandedbeta-sheetsurrounded by sevenalpha helicesand two one-turn helices. It is involved in the binding of magnesium ions (Mg2+) and GTP hydrolysis. GTP is joined to the protein through a nucleotide binding region, located between the 65th and 72nd amino acid.[4]
  • EH domain,between the 444th and 532nd amino acid. It is found in all of the EHD proteins. The fold consists of two helix-loop-helix connected by a short antiparallel beta-sheet. The targetpeptideis bound in a hydrophobic region between two alpha helices. Apart from an EF-hand domain, it can also includetyrosine phosphorylationsites andcoiled coils.This domain is often related to the regulation of protein transport,sortingand membrane trafficking.[5]
  • EF-hand,between the 476th and 511th amino acid. It forms part of the EH domain. It has a calcium ion (Ca2+) binding, between the 489th and 500th amino acid, which interacts selectively and non-covalently with calcium ions, attaching them to the protein.
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

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Protein post-translational modifications(PTM) increase the functional diversity of the proteome by the covalent addition of functional groups or proteins, by thehydrolysisofpeptide bondsthat linkamino acidstogether or by the degradation of different parts of the protein.[6]The EHD3 protein suffers three kinds of amino acid modifications:

  • Acetylation.It consists of attaching an acetyl group at the N-terminus.[7]Therefore, the first amino acid is an N-acetylmethionine.
  • Cross-link.It involves linking two proteins or two parts of the same protein with covalent bonds. In the case of EHD3, there are two cross-links which are isopeptide bonds between a lysine and a glycine. They are located in the 315th and 511th amino acid.
  • Phosphorylation.It consists of the addition of a phosphate group (HPO3). In EHD3, there are two serine phosphorylations; one in the 349th amino acid and other in the 456th.
Post-translational modifications of the EHD3.In red, acetylations. In pink, cross-links. And in purple, phosphorylations.

Functions

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

  • To take part inendocytic transport.The EHD-family proteins have been seen to have a direct relation with endocytic transport in the cell.EHD1(the closest paralog of EHD3)[9]is in charge of enabling membrane recycling by controlling the way out of internalized molecules from the ERC to the plasma membrane. It has also been found that these EHD proteins bind to the Rab11-effectorRab11-FIP2via EH-NPF interactions. These associations are affected by their ability to bindnucleotides.The role of EHD1 bonded to the Rab11-effector is clear (stated above), while there has not been found a clear relation between EHD3 and Rab11-FIP2. But when the EHD3 protein underwent a knockdown, the delivery of internalized transferrin and early endosomal proteins to the ERC was prevented, and even the subcellular location of Rab11-FIP2 changed. Therefore, a coordinated role for EHD proteins and Rab11-FIP2 has been found in mediating endocytic recycling and concretely for EHD3, early endosome to ERC transport.[10][11]
  • To control the membrane reorganization uponATP hydrolysis.[12]
  • To inducephosphatidic acidmembrane tubulation activity.[13]
  • To recycle the D1dopamine receptor.[14]
EHD3 can be mainly found in human heart and brain, as well as kidney, ovary and liver.[15]

Gene

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The gene that encodes the human EHD3 protein is located inchromosomenumber 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 their3'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

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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

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Mutagenesis

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  • Mutation in theposition 65(G → R): It is a change between a glycine and an arginine. Whereas between the 65th and the 72nd amino acid is located a nucleotide binding, a mutation in the first amino acid abolishes the ATP-binding
  • Mutation in theposition 203(V → P): A valine is substituted by a proline. It is located in the coiled coil of the dynamin-type guanine nucleotide-binding domain. It reduces oligomerization and interaction with Rab11-FIP2, a protein which regulates the transport of vesicles from the endosomal recycling compartment (ERC) to the plasma membrane.[17]
  • Mutation in theposition 315(K → R): An arginine replaces a lysine. It abolishes the function of the cross-link, which is located in the same amino acid. Therefore, the protein can notsumoylatethe R-511. Furthermore, it affects its localization in the tubular structures of the ERC.
  • Mutation in theposition 485(W → A): A tryptophan is changed by an alanine. Although it is not a coiled coil, it also abolishes interaction with Rab11-FIP2, just like the mutation in the position 203.
  • Mutation in theposition 511(K → R): in the same way as the mutation in the position 315, a lysine is substituted by an arginine and the cross-link is unable to do sumoylation. However, this cross-link is associated with R-315, instead of the R-511.[18]
EHD3 principal mutations.

Diseases

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The lack or malfunction of this protein in the human body can cause some diseases such asheart failure[19]or adepressive disorder.Losing EHD3 is also known to be an early step towardsgliomaformation.

Major Depressive Disorder (MDD)

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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. ThreeSNPshave 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

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

EHD3 gene has got functions as atumor suppressor geneand 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/G1cell cycle arrest andapoptotic 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

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  1. ^"EHD Home Page: An ATPase involved in membrane remodelling".www.endocytosis.org.Retrieved2016-10-15.
  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.Retrieved2016-10-15.
  4. ^EMBL-EBI, InterPro."Dynamin-type guanine nucleotide-binding (G) domain (IPR030381) < InterPro < EMBL-EBI".www.ebi.ac.uk.Retrieved2016-10-15.
  5. ^EMBL-EBI, InterPro."EH domain (IPR000261) < InterPro < EMBL-EBI".www.ebi.ac.uk.Retrieved2016-10-15.
  6. ^"Overview of Post-Translational Modifications (PTMs)".Thermo Fisher.
  7. ^"Acetylation".www.uniprot.org.Retrieved2016-10-16.
  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.PMID24306026.
  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.PMID12121420.
  10. ^Norris PR (1977)."Thermoacidophilic archaebacteria: potential applications".Biochemical Society Symposium.58(1): 171–80.PMC1445405.PMID1445405.
  11. ^"Ehd3 - EH domain-containing protein 3 - Mus musculus (Mouse) - Ehd3 gene & protein".www.uniprot.org.Retrieved2016-10-21.
  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.PMC4344897.PMID25686250.
  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.PMID12121420.
  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.PMC3417347.PMID21791287.
  15. ^"Tissue expression of EHD3 - Summary - The Human Protein Atlas".www.proteinatlas.org.Retrieved2016-10-21.
  16. ^"EHD3".www.genecards.org.Retrieved2016-10-17.
  17. ^"RAB11FIP2 - Rab11 family-interacting protein 2 - Homo sapiens (Human) - RAB11FIP2 gene & protein".www.uniprot.org.Retrieved2016-10-22.
  18. ^"EHD3 - EH domain-containing protein 3 - Homo sapiens (Human) - EHD3 gene & protein".www.uniprot.org.Retrieved2016-10-22.
  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.PMC3360944.PMID22406195.
  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.PMID24607927.S2CID28116425.
  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.PMID24306026.
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