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| | ==Solution NMR Structure of the Colied-coil PALB2 Homodimer== | | ==Solution NMR Structure of the Colied-coil PALB2 Homodimer== |
| - | <StructureSection load='6e4h' size='340' side='right' caption='[[6e4h]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | + | <StructureSection load='6e4h' size='340' side='right'caption='[[6e4h]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6e4h]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E4H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6E4H FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6e4h]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E4H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6E4H FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Palb2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr> | + | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6e4h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e4h OCA], [https://pdbe.org/6e4h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6e4h RCSB], [https://www.ebi.ac.uk/pdbsum/6e4h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6e4h ProSAT]</span></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=6e4h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e4h OCA], [http://pdbe.org/6e4h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6e4h RCSB], [http://www.ebi.ac.uk/pdbsum/6e4h PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6e4h ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PALB2_MOUSE PALB2_MOUSE]] Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks. Strongly stimulates the DNA strand-invasion activity of RAD51, stabilizes the nucleoprotein filament against a disruptive BRC3-BRC4 polypeptide and helps RAD51 to overcome the suppressive effect of replication protein A (RPA). Functionally cooperates with RAD51AP1 in promoting of D-loop formation by RAD51. Serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex which is essential for homologous recombination. Via its WD repeats is proposed to scaffold a HR complex containing RAD51C and BRCA2 which is thought to play a role in HR-mediated DNA repair. Essential partner of BRCA2 that promotes the localization and stability of BRCA2. Also enables its recombinational repair and checkpoint functions of BRCA2. May act by promoting stable association of BRCA2 with nuclear structures, allowing BRCA2 to escape the effects of proteasome-mediated degradation. Binds DNA with high affinity for D loop, which comprises single-stranded, double-stranded and branched DNA structures. May play a role in the extension step after strand invasion at replication-dependent DNA double-strand breaks; together with BRCA2 is involved in both POLH localization at collapsed replication forks and DNA polymerization activity (By similarity). | + | [https://www.uniprot.org/uniprot/PALB2_MOUSE PALB2_MOUSE] Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks. Strongly stimulates the DNA strand-invasion activity of RAD51, stabilizes the nucleoprotein filament against a disruptive BRC3-BRC4 polypeptide and helps RAD51 to overcome the suppressive effect of replication protein A (RPA). Functionally cooperates with RAD51AP1 in promoting of D-loop formation by RAD51. Serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex which is essential for homologous recombination. Via its WD repeats is proposed to scaffold a HR complex containing RAD51C and BRCA2 which is thought to play a role in HR-mediated DNA repair. Essential partner of BRCA2 that promotes the localization and stability of BRCA2. Also enables its recombinational repair and checkpoint functions of BRCA2. May act by promoting stable association of BRCA2 with nuclear structures, allowing BRCA2 to escape the effects of proteasome-mediated degradation. Binds DNA with high affinity for D loop, which comprises single-stranded, double-stranded and branched DNA structures. May play a role in the extension step after strand invasion at replication-dependent DNA double-strand breaks; together with BRCA2 is involved in both POLH localization at collapsed replication forks and DNA polymerization activity (By similarity). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Large Structures]] |
| - | [[Category: Bunting, S F]] | + | [[Category: Mus musculus]] |
| - | [[Category: Li, M]] | + | [[Category: Bunting SF]] |
| - | [[Category: Liu, G]] | + | [[Category: Li M]] |
| - | [[Category: Montelione, G T]] | + | [[Category: Liu G]] |
| - | [[Category: Song, F]] | + | [[Category: Montelione GT]] |
| - | [[Category: Swapna, G V.T]] | + | [[Category: Song F]] |
| - | [[Category: Xia, B]] | + | [[Category: Swapna GVT]] |
| - | [[Category: Antiparallel coiled coil]]
| + | [[Category: Xia B]] |
| - | [[Category: Dna damage repair]]
| + | |
| - | [[Category: Homologous recombination]]
| + | |
| - | [[Category: Oncoprotein]]
| + | |
| Structural highlights
Function
PALB2_MOUSE Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks. Strongly stimulates the DNA strand-invasion activity of RAD51, stabilizes the nucleoprotein filament against a disruptive BRC3-BRC4 polypeptide and helps RAD51 to overcome the suppressive effect of replication protein A (RPA). Functionally cooperates with RAD51AP1 in promoting of D-loop formation by RAD51. Serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex which is essential for homologous recombination. Via its WD repeats is proposed to scaffold a HR complex containing RAD51C and BRCA2 which is thought to play a role in HR-mediated DNA repair. Essential partner of BRCA2 that promotes the localization and stability of BRCA2. Also enables its recombinational repair and checkpoint functions of BRCA2. May act by promoting stable association of BRCA2 with nuclear structures, allowing BRCA2 to escape the effects of proteasome-mediated degradation. Binds DNA with high affinity for D loop, which comprises single-stranded, double-stranded and branched DNA structures. May play a role in the extension step after strand invasion at replication-dependent DNA double-strand breaks; together with BRCA2 is involved in both POLH localization at collapsed replication forks and DNA polymerization activity (By similarity).
Publication Abstract from PubMed
Deficits in DNA damage repair pathways are the root cause of several human cancers. In mammalian cells, DNA double-strand break repair is carried out by multiple mechanisms, including homologous recombination (HR). PALB2 (Partner and Localizer of BRCA2), which is an essential factor for HR, binds to the breast cancer susceptibility 1 (BRCA1) protein at DNA double-strand breaks. At the break site, PALB2 also associates with breast cancer susceptibility 2 (BRCA2) protein, to form a multi-protein complex that facilitates HR. The BRCA1-PALB2 interaction is mediated by association of predicted helical coiled-coil regions in both proteins. PALB2 can also homodimerize through the formation of a coiled coil, by self-association of helical elements at the N-terminus of the PALB2 protein, and this homodimerization has been proposed to regulate the efficiency of HR. We have produced a segment of PALB2 (PALB2cc), which forms alpha-helical structures, and which assembles into stable homodimers or heterodimers with a PALB2-interacting segment of BRCA1 (BRCA1cc). The three-dimensional structure of the homodimer formed by PALB2cc was determined by solution NMR spectroscopy. This PALB2cc homodimer is a classical anti-parallel coiled-coil leucine zipper. NMR chemical shift perturbation studies were used to study dimer formation for both the PALB2cc homodimer and the PALB2cc:BRCA1cc heterodimer. Mutation of residue Leu24 of PALB2cc significantly reduces its homodimer stability, but has a more modest effect on the stability of the heterodimer formed between PALB2cc and BRCA1cc. We show that mutation of Leu24 leads to genomic instability and reduced cell viability after treatment with agents that induce DNA double-strand breaks. These studies may allow the identification of distinct mutations of PALB2 which selectively disrupt homodimeric versus heterodimeric interactions, and reveal the specific role of PALB2 homodimerization in HR.
Antiparallel Coiled-Coil Interactions Mediate Homodimerization of the DNA Damage Repair Protein, PALB2.,Song F, Li M, Liu G, Gurla S, Daigham N, Xia B, Montelione G, Bunting S Biochemistry. 2018 Oct 5. doi: 10.1021/acs.biochem.8b00789. PMID:30289697[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Song F, Li M, Liu G, Gurla S, Daigham N, Xia B, Montelione G, Bunting S. Antiparallel Coiled-Coil Interactions Mediate Homodimerization of the DNA Damage Repair Protein, PALB2. Biochemistry. 2018 Oct 5. doi: 10.1021/acs.biochem.8b00789. PMID:30289697 doi:http://dx.doi.org/10.1021/acs.biochem.8b00789
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