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6fx5

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MITF dimerization mutant

Structural highlights

6fx5 is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	Mitf, Bw, Mi, Vit (LK3 transgenic mice)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[MITF_MOUSE] Defects in Mitf are the cause of microphthalmia (mi), a condition characterized by loss of pigmentation; reduced eye size; failure of secondary bone resorption; reduced numbers of mast cells; early onset of deafness, and which gives rise to a number of different phenotypes. Among them, microphthalmia-eyeless white (mi-ew) has a normal appearance at the heterozygous state, but shows white coat; eyes almost absent and eyelids never open at homozygosity. Microphthalmia-black and white spot (mi-bws) is normal at heterozygosity, and presents white spots and black eyes at homozygous state. Microphthalmia-white (mi-wh) has reduced coat color and eye pigmentation; spots on toes, tail and belly; inner ear defects at heterozygosity, and at homozygosity shows white coat; eyes small and inner iris slightly pigmented; spinal ganglia, adrenal medulla and dermis smaller than normal, and inner ear defects. Microphthalmia-vitiligo (mi-vi) has normal phenotype at heterozygosity, but shows gradual depigmentation of coat, skin and eyes; and retinal degeneration at homozygosity. Microphthalmia-spotted (mi-sp) shows normal phenotype; at homozygosity, however, tyrosinase activity in skin is reduced. Microphthalmia-defective irism (mi-di) has reduced retinal pigmentation at heterozygosity and shows white coat; eyes of reduced sized and possible mild osteoporosis at homozygosity. Microphthalmia-cloudy eyed (mi-ce) has a normal appearance at the heterozygous state, but shows white coat; eyes of reduced size and unpigmented at homozygosity. Microphthalmia-red-eyed white (mi-rw) has a normal appearance at the homozygous state, but shows white coat with one or more pigmented spots around the head/and or tail; eyes are small and red at heterozygosity. Microphthalmia-black-eyed white (mi-bw) shows a white coat but normal sized eyes which reamin black at homozygosity.

Function

[MITF_MOUSE] Transcription factor that regulates the expression of genes with essential roles in cell differentiation, proliferation and survival. Binds to symmetrical DNA sequences (E-boxes) (5'-CACGTG-3') found in the promoters of target genes, such as BCL2 and tyrosinase (TYR). Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Plays a critical role in the differentiation of various cell types, such as neural crest-derived melanocytes, mast cells, osteoclasts and optic cup-derived retinal pigment epithelium.

Publication Abstract from PubMed

Interrupted dimeric coiled coil segments are found in a broad range of proteins and generally confer selective functional properties such as binding to specific ligands. However, there is only one documented case of a basic-helix-loop-helix leucine zipper transcription factor-microphthalmia-associated transcription factor (MITF)-in which an insertion of a three-residue stammer serves as a determinant of conditional partner selectivity. To unravel the molecular principles of this selectivity, we have analyzed the high-resolution structures of stammer-containing MITF and an engineered stammer-less MITF variant, which comprises an uninterrupted symmetric coiled coil. Despite this fundamental difference, both MITF structures reveal identical flanking in-phase coiled coil arrangements, gained by helical over-winding and local asymmetry in wild-type MITF across the stammer region. These conserved structural properties allow the maintenance of a proper functional readout in terms of nuclear localization and binding to specific DNA-response motifs regardless of the presence of the stammer. By contrast, MITF heterodimer formation with other bHLH-Zip transcription factors is only permissive when both factors contain either the same type of inserted stammer or no insert. Our data illustrate a unique principle of conditional partner selectivity within the wide arsenal of transcription factors with specific partner-dependent functional readouts.

Mechanism of conditional partner selectivity in MITF/TFE family transcription factors with a conserved coiled coil stammer motif.,Pogenberg V, Ballesteros-Alvarez J, Schober R, Sigvaldadottir I, Obarska-Kosinska A, Milewski M, Schindl R, Ogmundsdottir MH, Steingrimsson E, Wilmanns M Nucleic Acids Res. 2019 Nov 28. pii: 5644993. doi: 10.1093/nar/gkz1104. PMID:31777941^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Pogenberg V, Ballesteros-Alvarez J, Schober R, Sigvaldadottir I, Obarska-Kosinska A, Milewski M, Schindl R, Ogmundsdottir MH, Steingrimsson E, Wilmanns M. Mechanism of conditional partner selectivity in MITF/TFE family transcription factors with a conserved coiled coil stammer motif. Nucleic Acids Res. 2019 Nov 28. pii: 5644993. doi: 10.1093/nar/gkz1104. PMID:31777941 doi:http://dx.doi.org/10.1093/nar/gkz1104

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6fx5"

@@ Line 3: / Line 3: @@
 <StructureSection load='6fx5' size='340' side='right'caption='[[6fx5]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6fx5]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FX5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FX5 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6fx5]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FX5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FX5 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Mitf, Bw, Mi, Vit ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6fx5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fx5 OCA], [http://pdbe.org/6fx5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fx5 RCSB], [http://www.ebi.ac.uk/pdbsum/6fx5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fx5 ProSAT]</span></td></tr>
 </table>
@@ Line 11: / Line 12: @@
 == Function ==
 [[http://www.uniprot.org/uniprot/MITF_MOUSE MITF_MOUSE]] Transcription factor that regulates the expression of genes with essential roles in cell differentiation, proliferation and survival. Binds to symmetrical DNA sequences (E-boxes) (5'-CACGTG-3') found in the promoters of target genes, such as BCL2 and tyrosinase (TYR). Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Plays a critical role in the differentiation of various cell types, such as neural crest-derived melanocytes, mast cells, osteoclasts and optic cup-derived retinal pigment epithelium.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Interrupted dimeric coiled coil segments are found in a broad range of proteins and generally confer selective functional properties such as binding to specific ligands. However, there is only one documented case of a basic-helix-loop-helix leucine zipper transcription factor-microphthalmia-associated transcription factor (MITF)-in which an insertion of a three-residue stammer serves as a determinant of conditional partner selectivity. To unravel the molecular principles of this selectivity, we have analyzed the high-resolution structures of stammer-containing MITF and an engineered stammer-less MITF variant, which comprises an uninterrupted symmetric coiled coil. Despite this fundamental difference, both MITF structures reveal identical flanking in-phase coiled coil arrangements, gained by helical over-winding and local asymmetry in wild-type MITF across the stammer region. These conserved structural properties allow the maintenance of a proper functional readout in terms of nuclear localization and binding to specific DNA-response motifs regardless of the presence of the stammer. By contrast, MITF heterodimer formation with other bHLH-Zip transcription factors is only permissive when both factors contain either the same type of inserted stammer or no insert. Our data illustrate a unique principle of conditional partner selectivity within the wide arsenal of transcription factors with specific partner-dependent functional readouts.
+Mechanism of conditional partner selectivity in MITF/TFE family transcription factors with a conserved coiled coil stammer motif.,Pogenberg V, Ballesteros-Alvarez J, Schober R, Sigvaldadottir I, Obarska-Kosinska A, Milewski M, Schindl R, Ogmundsdottir MH, Steingrimsson E, Wilmanns M Nucleic Acids Res. 2019 Nov 28. pii: 5644993. doi: 10.1093/nar/gkz1104. PMID:31777941<ref>PMID:31777941</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6fx5" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
 [[Category: Large Structures]]
+[[Category: Lk3 transgenic mice]]
 [[Category: Milewski, M]]
 [[Category: Pogenberg, V]]

6fx5

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Current revision

MITF dimerization mutant

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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