View source for 8yap


==Structure of human PALB2 coiled-coil domain==
<StructureSection load='8yap' size='340' side='right'caption='[[8yap]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8yap]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8YAP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8YAP FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 10 models</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=8yap FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8yap OCA], [https://pdbe.org/8yap PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8yap RCSB], [https://www.ebi.ac.uk/pdbsum/8yap PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8yap ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/PALB2_HUMAN PALB2_HUMAN] Defects in PALB2 are a cause of susceptibility to breast cancer (BC) [MIM:[https://omim.org/entry/114480 114480]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Note=Breast cancer susceptibility is strongly associated with PALB2 truncating mutations. Conversely, rare missense mutations do not strongly influence breast cancer risk (PubMed:22241545).  Defects in PALB2 are the cause of Fanconi anemia complementation group N (FANCN) [MIM:[https://omim.org/entry/610832 610832]. It is a disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair.<ref>PMID:17200672</ref>   Defects in PALB2 are the cause of pancreatic cancer type 3 (PNCA3) [MIM:[https://omim.org/entry/613348 613348]. It is a malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue.<ref>PMID:19264984</ref> 
== Function ==
[https://www.uniprot.org/uniprot/PALB2_HUMAN PALB2_HUMAN] Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks. Serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex which is essential for homologous recombination. 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. 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.<ref>PMID:16793542</ref> <ref>PMID:19423707</ref> <ref>PMID:19369211</ref> <ref>PMID:20871615</ref> <ref>PMID:20871616</ref> 
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== Publication Abstract from PubMed ==
The tumor suppressor PALB2 is a key player in the Homologous Recombination (HR) pathway, functionally connecting BRCA proteins at the DNA damage site. PALB2 forms homodimers via its coiled-coil domain, and during HR, it forms a heterodimeric complex with BRCA1 using the same domain. However, the structural details of the human PALB2 coiled-coil domain are unknown. Several missense variants have been reported in the coiled-coil domain. The structure-function relationship of these variants is poorly understood, posing a challenge to genetic counseling. In this study, we present the solution structure of the human PALB2 coiled-coil domain, which forms an antiparallel homodimer. We then use this structure to investigate the impact of a few well-characterized missense mutations on the fold and interactions of the PALB2 coiled-coil domain. Our findings reveal a strong correlation between the structural impact of mutations and their efficiency in homologous recombination, suggesting that our approach can be applied to study other genetic variations in PALB2. These findings hold promise for improving genetic counseling and advancing cancer research.

Structural analysis of genetic variants of the human tumor suppressor Palb2 coiled-coil domain.,Reddy PP, Phale A, Das R Biosci Rep. 2025 Jan 2:BSR20241173. doi: 10.1042/BSR20241173. PMID:39745016<ref>PMID:39745016</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Das R]]
[[Category: Reddy PP]]