WIF domain

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WIF protein domain
Identifiers
SymbolWIF
Pfam PF02019
InterPro IPR003306
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

In molecular biology, the protein domain, WIF N-terminal refers to the N terminal domain of the protein, WIF. It stands for, Wnt-inhibitory factor, whereby wnt is a signalling molecule also known as wingless. Wnt is a molecule in the wnt signaling pathway. The WIF domain binds to the wnt ligand since it inhibits it.

Contents

Function

The function of the WIF domain is to bind to Wnt ligands and prevent the downstream signal transduction. Inevitably, this prevents cell development in embryogenesis and cancer.

Structure

The domain is extracellular, meaning it is on the outside of the cell and it contains two conserved cysteines that form a disulphide bridge. [1] This domain is Wnt binding in WIF, and it has been suggested that RYK may also bind to Wnt. [2] More specifically, crystal structure of WIF-1(WD) show a binding site for phospholipid; two acyl chains extending deep into the domain, and a head group is exposed to the surface. [1]

Wnt Ligand

Wnt proteins constitute a large family of secreted molecules that are involved in intercellular signalling during development. The name derives from the first 2 members of the family to be discovered: int-1 (mouse) and wingless (Drosophila). [3] It is now recognised that Wnt signalling controls many cell fate decisions in a variety of different organisms, including mammals. [4] Wnt signalling has been implicated in tumourigenesis, early mesodermal patterning of the embryo, morphogenesis of the brain and kidneys, regulation of mammary gland proliferation and Alzheimer's disease. [5] [6]

Wnt-mediated signalling is believed to proceed initially through binding to cell surface receptors of the frizzled family; the signal is subsequently transduced through several cytoplasmic components to B-catenin, which enters the nucleus and activates the transcription of several genes important in development. [7] More recently, however, several non-canonical Wnt signalling pathways have been elucidated that act independently of B-catenin. Members of the Wnt gene family are defined by their sequence similarity to mouse Wnt-1 and Wingless in Drosophila. They encode proteins of ~350-400 residues in length, with orthologues identified in several, mostly vertebrate, species. Very little is known about the structure of Wnts as they are notoriously insoluble; but they share the following features characteristics of secretory proteins: a signal peptide, several potential N-glycosylation sites and 22 conserved cysteines [3] that are probably involved in disulphide bonds. The Wnt proteins seem to adhere to the plasma membrane of the secreting cells and are therefore likely to signal over only few cell diameters. Fifteen major Wnt gene families have been identified in vertebrates, with multiple subtypes within some classes.

Related Research Articles

<span class="mw-page-title-main">Paracrine signaling</span>

Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.

<span class="mw-page-title-main">Morphogen</span> Biological substance that guides development by non-uniform distribution

A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the various specialized cell types within a tissue. More specifically, a morphogen is a signaling molecule that acts directly on cells to produce specific cellular responses depending on its local concentration.

The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. Diseases associated with the malfunction of this pathway include cancer.

Frzb is a Wnt-binding protein especially important in embryonic development. It is a competitor for the cell-surface G-protein receptor Frizzled.

<span class="mw-page-title-main">Catenin beta-1</span> Mammalian protein found in Homo sapiens

Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the CTNNB1 gene.

<span class="mw-page-title-main">Frizzled</span> Family of G-protein coupled receptor proteins

Frizzled is a family of atypical G protein-coupled receptors that serve as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol.

<span class="mw-page-title-main">Alpha catenin</span> Primary protein link between cadherins and the actin cytoskeleton

Alpha-catenin functions as the primary protein link between cadherins and the actin cytoskeleton. It has been reported that the actin binding proteins vinculin and alpha-actinin can bind to alpha-catenin. It has been suggested that alpha-catenin does not bind with high affinity to both actin filaments and the E-cadherin-beta-catenin complex at the same time. It has been observed that when alpha-catenin is not in a molecular complex with beta-catenin, it dimerizes and functions to regulate actin filament assembly, possibly by competing with Arp2/3 protein. Alpha catenin exhibits significant protein dynamics. However, a protein complex including a cadherin, actin, beta-catenin and alpha-catenin has not been isolated.

<span class="mw-page-title-main">AXIN1</span> Protein-coding gene in the species Homo sapiens

Axin-1 is a protein that in humans is encoded by the AXIN1 gene.

<span class="mw-page-title-main">Proto-oncogene Wnt-1</span> Protein-coding gene in the species Homo sapiens

Proto-oncogene Wnt-1, or Proto-oncogene Int-1 homolog is a protein that in humans is encoded by the WNT1 gene.

<span class="mw-page-title-main">Frizzled-5</span> Protein-coding gene in the species Homo sapiens

Frizzled-5(Fz-5) is a protein that in humans is encoded by the FZD5 gene.

<span class="mw-page-title-main">Frizzled-8</span> Protein-coding gene in the species Homo sapiens

Frizzled-8(Fz-8) is a protein that in humans is encoded by the FZD8 gene.

<span class="mw-page-title-main">IQGAP1</span>

Ras GTPase-activating-like protein IQGAP1 (IQGAP1) also known as p195 is a ubiquitously expressed protein that in humans is encoded by the IQGAP1 gene. IQGAP1 is a scaffold protein involved in regulating various cellular processes ranging from organization of the actin cytoskeleton, transcription, and cellular adhesion to regulating the cell cycle.

<span class="mw-page-title-main">DVL1</span> Human protein and coding gene

Segment polarity protein dishevelled homolog DVL-1 is a protein that in humans is encoded by the DVL1 gene.

<span class="mw-page-title-main">Secreted frizzled-related protein 1</span> Protein-coding gene in the species Homo sapiens

Secreted frizzled-related protein 1, also known as SFRP1, is a protein which in humans is encoded by the SFRP1 gene.

<span class="mw-page-title-main">LRP6</span> Protein-coding gene in the species Homo sapiens

Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.

<span class="mw-page-title-main">WIF1</span> Protein-coding gene in the species Homo sapiens

Wnt inhibitory factor 1 is a protein that in humans is encoded by the WIF1 gene. WIF1 is a lipid-binding protein that binds to Wnt proteins and prevents them from triggering signalling.

<span class="mw-page-title-main">WNT2</span> Protein-coding gene in the species Homo sapiens

Wingless-type MMTV integration site family, member 2, also known as WNT2, is a human gene.

<span class="mw-page-title-main">TCF/LEF family</span> Group of genes

The TCF/LEF family is a group of genes that encode transcription factors which bind to DNA through a SOX-like high mobility group domain. They are involved in the Wnt signaling pathway, particularly during embryonic and stem-cell development, but also had been found to play a role in cancer and diabetes. TCF/LEF factors recruit the coactivator beta-catenin to enhancer elements of genes they target. They can also recruit members of the Groucho family of corepressors.

Naked cuticle (Nkd) is a conserved family of intracellular proteins encoded in most animal genomes. The original mutants were discovered by 1995 Nobel laureates Christiane Nüsslein-Volhard and Eric F. Wieschaus and colleagues in their genetic screens for pattern-formation mutants in the fruit fly Drosophila melanogaster. The Nkd gene family was first cloned in the laboratory of Matthew P. Scott. Like many cleverly named fly mutants, the name "naked cuticle" derives from the fact that mutants lack most of the hair-like protrusions from their ventral cuticle and thus appear "naked".

References

  1. 1 2 Malinauskas T, Aricescu AR, Lu W, Siebold C, Jones EY (2011). "Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1". Nat Struct Mol Biol. 18 (8): 886–93. doi:10.1038/nsmb.2081. PMC   3430870 . PMID   21743455.
  2. Patthy L (January 2000). "The WIF module". Trends Biochem. Sci. 25 (1): 12–3. doi:10.1016/s0968-0004(99)01504-2. PMID   10637605.
  3. 1 2 Wodarz A, Nusse R (1998). "Mechanisms of Wnt signaling in development". Annu. Rev. Cell Dev. Biol. 14: 59–88. doi:10.1146/annurev.cellbio.14.1.59. PMID   9891778.
  4. Bejsovec A (September 1999). "Wnt signalling shows its versatility". Curr. Biol. 9 (18): R684-7. doi: 10.1016/S0960-9822(99)80439-4 . PMID   10508601. S2CID   14573233.
  5. De Ferrari GV, Inestrosa NC (August 2000). "Wnt signaling function in Alzheimer's disease". Brain Res. Brain Res. Rev. 33 (1): 1–12. doi:10.1016/S0165-0173(00)00021-7. PMID   10967351. S2CID   25724572.
  6. Semënov MV, Snyder M (June 1997). "Human dishevelled genes constitute a DHR-containing multigene family". Genomics. 42 (2): 302–10. doi: 10.1006/geno.1997.4713 . PMID   9192851.
  7. Peifer M, Polakis P (March 2000). "Wnt signaling in oncogenesis and embryogenesis--a look outside the nucleus". Science. 287 (5458): 1606–9. Bibcode:2000Sci...287.1606P. doi:10.1126/science.287.5458.1606. PMID   10733430.
This article incorporates text from the public domain Pfam and InterPro: IPR003306